Cephem and cepham compounds

ABSTRACT

This invention relates to novel 7-thiadiazol-oxyimino-3-cephem and cepham 4-carboxylic acid compounds of high antimicrobial activity.

This application is a continuation in part of parent application Ser.No. 160,904, filed June 18, 1980, which in turn is a continuation inpart of parent application Ser. No. 128,260, filed Mar. 7, 1980, nowU.S. Pat. No. 4,331,665, which in turn is a continuation in part ofparent application Ser. No. 116,984, filed Jan. 30, 1980, now U.S. Pat.No. 4,332,798, which in turn is a continuation in part of parentapplication Ser. No. 108,161, filed Dec. 28, 1979, now abandoned.

This invention relates to new cephem compounds. More particularly, itrelates to new 7-substituted-3-cephem and cepham-4-carboxylic acid andpharmaceutically acceptable salt thereof, which have antimicrobialactivities, and processes for preparation thereof, to intermediate forpreparing the same and processes for preparation thereof, and topharmaceutical composition comprising the same and methods of using thesame prophylactically and therapeutically for treatment of infectiousdiseases in human being and animals.

Accordingly, the objects of this invention are to provide:

new 7-substituted-3-cephem and cepham-4-carboxylic acid andpharmaceutically acceptable salt thereof, which exhibit excellentantimicrobial activities against a wide variety of pathogenicmicroorganisms including Gram negative and Gram positive bacteria,

processes for preparation of the same,

pharmaceutical composition comprising one of the same as an activeingredient, and

a method of using the same prophylactically and therapeutically fortreatment of infectious diseases caused by pathogenic microorganisms inhuman being and animals; and further

intermediate to be used for preparation of pharmaceutically active7-substituted-3-cephem and cepham-4-carboxylic acid or pharmaceuticallyacceptable salt thereof and processes for preparation thereof.

The object 7-substituted-3-cephem and cepham-4-carboxylic acid is noveland can be represented by the following general formula (I). ##STR1##wherein R¹ is amino or a protected amino,

R² is hydrogen, acyl, aryl which may be substituted with suitablesubstituent(s), lower alkyl substituted with suitable substituent(s),lower alkenyl, lower alkynyl, cycloalkyl which may be substituted withsuitable substituent(s), cyclo(lower)alkenyl, or S or O containing5-membered heterocyclic group substituted with oxo group(s),

R³ is hydrogen or lower alkyl,

R⁴ is hydrogen; acyloxy(lower)alkyl; acylthio(lower)alkyl;pyridinium(lower)alkyl which may be substituted with suitablesubstituent(s); a heterocyclicthio(lower)alkyl which may be substitutedwith suitable substituent(s); lower alkyl; halogen; hydroxy; orthiazolium(lower)alkyl which may be substituted with suitablesubstituent(s); and

R⁵ is carboxy or a protected carboxy,

wherein R⁵ is COO⁻ when R⁴ is pyridinium(lower)alkyl which may besubstituted with suitable substituent(s) or thiazolium(lower)alkyl whichmay be substituted with suitable substituent(s),

and the heavy solid line means single or double bond.

According to the present invention, the object 7-substituted-3-cephemand cepham-4-carboxylic acid (I) can be prepared by the followingprocesses. ##STR2## wherein R¹, R², R³, R⁴ and R⁵ are each as definedabove;

R^(5a) is a protected carboxy;

R^(4b) is pyridine which may be substituted with suitablesubstituent(s), thiazole which may be substituted with suitablesubstituent(s) or a group of the formula: R^(4e) --SH wherein

R^(4e) is acyl or a heterocyclic group which may be substituted withsuitable substituent(s);

A is lower alkylene;

R^(4c) is a heterocyclicthio(lower)alkyl substituted with protectedamino(lower)alkyl;

R^(4d) is a heterocyclicthio(lower)alkyl substituted withamino(lower)alkyl;

R^(2a) is a protective group of hydroxy;

R^(4a) is a group which can be substituted with a group of the formula:R^(4f) wherein R^(4f) is pyridinium which may be substituted withsuitable substituent(s), thiazolium which may be substituted withsuitable substituent(s), or a group of the formula: --S-R^(4e) wherein

R^(4e) is as defined above;

R^(4f) is as defined above;

R^(2b) is protected amino(lower)alkyl;

R^(2c) is amino(lower)alkyl;

R^(2d) is protected carboxy(lower)alkyl, ar(lower)alkyl substituted withprotected carboxy or cycloalkyl substituted with protected carboxy;

R^(2e) is carboxy(lower)alkyl, ar(lower)alkyl substituted with carboxyor cycloalkyl substituted with carboxy;

R⁸ is an ester moiety of an esterified carboxy represented by a group ofthe formula: --COOR⁸,

R^(2f) is protected amino(lower)alkyl or ar(lower)alkyl substituted withprotected amino(lower)alkyl, and

R^(2g) is amino(lower)alkyl or ar(lower)alkyl substituted withamino(lower)alkyl.

Among the starting compounds of the present invention, the compound(III) is novel and can be prepared by the following preparations.##STR3## wherein R², R^(2a), R^(2f), R^(2g) and R¹ are each as definedabove, R^(2h) is aryl which may be substituted with suitablesubstituent(s) or cycloalkyl which may be substituted with suitablesubstituent(s), Z is carboxy or protected carboxy, R¹⁰ is protectedamino(C₃ -C₆)alkyl,

R¹¹ is amino(C₃ -C₆)alkyl,

R⁶ is a protective group of carboxy,

M is an alkali metal,

X is hydroxy or its reactive derivative,

R⁹ is amino having a protective group,

R^(1a) is a protected amino and

R⁷ is lower alkyl.

In the object compound (I) and the starting compound (III), the partialstructure represented by the formula: ##STR4## is to be understood toinclude both of the geometrical structures represented by the formulae:##STR5## In this specification, with regard to all the compounds havingthe above mentioned partial structure, the compounds having thegeometrical structure shown by the formula (A) are referred to as "synisomer" and the compounds having the alternative one shown by theformula (A') as "anti isomer".

Regarding the object compound of the formula (I) and the startingcompound of the formula (III) as mentioned above, it is also to beunderstood that said object and starting compounds may includetautomeric isomers relating to their thiadiazolyl group. That is, incase that the group represented by the formula: ##STR6## (wherein R¹ isamino or a protected amino) in formula of said object and startingcompounds take the formula: ##STR7## (wherein R¹ is as defined above),said group of the formula: ##STR8## may be also alternativelyrepresented by its tautomeric formula: ##STR9## (wherein R^(1') is iminoor a protected imino). That is, both of the said group (B) and (B') maybe in the state of equilibrium as so-called tautomeric forms which canbe represented by the following equilibrium: ##STR10## (wherein R¹ andR^(1') are each as defined above).

In the present specification including claims and examples, the objectand starting compounds having said group are represented by using one ofthe expressions therefor, namely the formula: ##STR11## only for theconvenient sake.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and may include an inorganic salt, forexample, a metal salt such as an alkali metal salt (e.g., sodium salt,potassium salt, etc.) and an alkaline earth metal salt (e.g., calciumsalt, magnesium salt, etc.), ammonium salt etc.; an organic salt, forexample, an organic amine salt (e.g., trimethylamine salt, triethylaminesalt, pyridine salt, procaine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylene-diamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt, phenylethylbenzylamine salt;dibenzylethylenediamine salt, etc.) etc.: an organic carboxylic orsulfonic acid salt (e.g., formate, acetate, maleate, tartrate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); aninorganic acid salt (e.g., hydrochloride, hydrobromide, sulfate,phosphate, etc.); a salt with a basic or acidic amino acid (e.g.,arginine, aspartic acid, glutamic acid, lysine, etc.) and the like.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term "lower" is used to intend a group having 1 to 6 carbon atom(s),unless otherwise provided.

Suitable protected amino may include an acylamino and amino groupsubstituted by a conventional proptective group other than the acylgroup, such as ar(lower)alkyl(e.g., benzyl, trityl, etc.)ar(lower)alkylidene(e.g., benzylidene, etc.), lower alkylidenesubstituted with lower alkoxycarbonyl or di(lower)alkylamino(e.g.,1-ethoxycarbonyl-2-propylidene, dimethylaminomethylene, etc.) or thelike.

Suitable protected imino may include an acylimino and imino groupsubstituted by a conventional protective group other than the acyl groupsuch as aforesaid ar(lower)alkyl or the like.

Suitable acyl and acyl moiety in the terms "acylamino", "acylimino","acyloxy(lower)alkyl" and "acylthio(lower)alkyl" may include carbamoyl,aliphatic acyl group and acyl group containing an aromatic orheterocyclic ring. And, suitable examples of the said acyl may be loweralkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.), preferably one having 1to 4 carbon atom(s), more preferably one having 1 to 2 carbon atom(s);

lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), preferably one having 3 to6 carbon atoms;

lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl, propanesulfonyl,isopropanesulfonyl, butanesulfonyl, etc.);

arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g.,benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.);

ar(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl; etc.);cyclo(lower)alkyl(lower)alkanoyl(e.g. cyclohexylacetyl,cyclopentylacetyl, etc.);

ar(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl,etc.); and the like.

The acyl and acyl moiety as stated above may have 1 to 3 suitablesubstituent(s) such as halogen (e.g., chlorine, bromine, iodine orfluorine), hydroxy, cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, etc.), lower alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, etc.), lower alkenyl (e.g., vinyl, allyl, etc.), aryl(e.g., phenyl, tolyl, etc.), amino, protected amino, acyl as mentionedabove, or the like.

Preferable example of acyl having said substituent(s) may bedi(lower)alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,dipropylcarbamoyl etc.), phenyl(lower)alkanoyl substituted with amino orlower alkoxycarbonylamino, cyclo(lower)alkyl(lower)alkanoyl substitutedwith amino, lower alkanoyl(lower)alkanoyl(e.g., acetylacetyl,acetylpropionyl, etc.), etc.

Suitable example of acyl for R² may include halo(lower)alkanoyl, morepreferably dihalo(lower)alkanoyl (e.g., dichloroacetyl, dibromoacetyl,etc.) and the like.

Suitable aryl may include phenyl, tolyl, xylyl, mesityl, cumenyl and thelike, and said aryl group may be substituted with 1 to 3 suitablesubstituent(s) such as halogen(e.g., chlorine, bromine, fluorine oriodine), nitro, lower alkoxy(e.g., methoxy, ethoxy, propoxy, butoxy,pentyloxy, hexyloxy, etc.) preferably one having 1 to 4 carbon atom(s),halo(lower)alkyl (e.g., chloromethyl, dichloromethyl, trichloromethyl,trifluoromethyl, trichloroethyl, etc.) preferably one having 1 to 3carbon atom(s), protected carboxy as illustrated below, preferably loweralkoxycarbonyl, more preferably one having 2 to 4 carbon atoms, or thelike.

Suitable lower alkyl and lower alkyl moiety is the terms"acyloxy(lower)alkyl", "acylthio(lower)alkyl" "pyridinium(lower)alkyl","protected amino(lower)alkyl", "amino(lower)alkyl", "protectedcarboxy(lower)alkyl", "carboxy(lower)alkyl","heterocycliothio(lower)alkyl", "ar(lower)alkyl" and"thiazolium(lower)alkyl" may include straight or branched one having 1to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, tert-pentyl, hexyl or the like.

Suitable substituent(s) in the term "lower alkyl substituted withsuitable substituent(s)" may include halogen (e.g. chlorine, bromine,fluorine or iodine); cyano; carboxy; protected carboxy as mentionedbelow; lower alkylthio (e.g., methylthio, ethylthio, propylthio,butylthio, etc.); aryl (e.g., phenyl, tolyl, xylyl, mesityl, cumenyl,etc.); aryloxy (e.g., phenoxy, tolyloxy, mesityloxy, etc.); aforesaidacyl; lower alkoxy(lower)alkoxy (e.g., methoxymethoxy, methoxyethoxy,ethoxyethoxy, propoxyethoxy, butoxyethoxy, pentyloxymethoxy,hexyloxymethoxy, hexyloxyethoxy, etc.); protected amino as mentionedabove, preferably acylamino, more preferably lower alkoxycarbonylamino,aryl(lower)alkanoylamino substituted with amino or loweralkoxycarbonylamino, cyclo(lower)alkyl(lower)alkanoylamino substitutedwith amino; amino; or the like, wherein the afore-said aryl group beingthe substituent(s) on lower alkyl may be substituted withamino(lower)alkyl (e.g., aminomethyl, aminoethyl, aminopropyl, etc.) orprotected amino(lower)alkyl; and suitable number of substituent(s) onlower alkyl group may be 1 to 3.

Suitable protected carboxy may include esterified carboxy in which saidester may be the ones such as lower alkyl ester (e.g., methyl ester,ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester,1-cyclopropylethyl ester, etc.), wherein lower alkyl moiety may bepreferably one having 1 to 4 carbon atom(s); lower alkenyl ester (e.g.,vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynylester, propynyl ester, etc.); mono(or di or tri)-halo(lower)alkyl ester(e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);

lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester,pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester,2-propionyloxyethyl ester, 1-isobutyryloxyethyl ester, etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester etc.);

ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester which may besubstituted with one or more suitable substituent(s) (e.g., benzylester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester,trityl ester, diphenylmethyl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylbenzyl ester,etc.);

lower alkoxycarbonyloxy(lower)alkyl ester(e.g., methoxycarbonyloxymethylester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester,etc.) which may be substituted with azido;

a heterocyclic ester, preferably benzotetrahydrofuryl ester which may besubstituted with oxo group, more preferably phthalidyl ester;

aroyloxy(lower)alkyl ester (e.g., benzoyloxymethyl ester,benzoyloxyethyl ester, toluoyloxyethyl ester, etc.);

aryl ester which may have one or more suitable substituent(s) (e.g.,phenyl ester, tolyl ester, tertiary-butylphenyl ester, xylyl ester,mesityl ester, cumenyl ester, etc.), and the like.

Preferable example of protected carboxy may be lower alkoxycarbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.) having 2to 7 carbon atoms, preferably one having 2 to 5 carbon atoms,phenyl(lower)alkoxycarbonyl which may be substituted with nitro (e.g.,4-nitrobenzyloxycarbonyl, benzyloxycarbonyl,4-nitrophenethyloxycarbonyl, etc.),

lower alkanoyloxy(lower)alkoxycarbonyl (e.g., acetoxymethoxycarbonyl,pivaloyloxymethoxycarbonyl, hexanoyloxymethoxycarbonyl,1-acetoxyethoxycarbonyl, 1-acetoxypropoxycarbonyl,1-isobutyryloxyethoxycarbonyl, etc.) preferably one having 3 to 8 carbonatoms;

lower alkoxycarbonyloxy(lower)alkoxycarbonyl (e.g.,ethoxycarbonyloxyethoxycarbonyl, ethoxycarbonyloxypropoxycarbonyl, etc.)which may be substituted with azido, preferably one having 5 to 7 carbonatoms;

phthalidyloxycarbonyl; and

aroyloxy(lower)alkoxycarbonyl(e.g., benzoyloxymethoxycarbonyl,benzoyloxyethoxycarbonyl, etc.).

Suitable lower alkenyl may include vinyl, allyl, isopropenyl,1-propenyl, 2-butenyl, 3-pentenyl and the like, preferably one having 2to 4 carbon atoms.

Suitable lower alkynyl may include one having 2 to 6 carbon atoms, forexample, ethynyl, 2-propynyl, 2-butynyl, 3-pentynyl, 3-hexynyl, or thelike, preferably one having 2 to 4 carbon atoms.

Suitable cycloalkyl may include one having 3 to 8 carbon atoms, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,or the like, preferably one having 4 to 7 carbon atoms.

Suitable substituent(s) on cycloalkyl can be referred to the ones asexemplified for substituent(s) on lower alkyl, and preferably carboxy orprotected carboxy.

Suitable cyclo(lower)alkenyl may include one having 3 to 6 carbon atoms,for example, cyclopentenyl, cyclohexenyl, or the like, preferably onehaving 5 or 6 carbon atoms.

Suitable S or O containing 5-membered heterocyclic group may includesaturated or unsaturated one, for example, dihydrofuryl,tetrahydrofuryl, thiolanyl or the like, which is substituted with 1 or 2oxo group(s).

Suitable heterocyclic group and heterocyclic moiety in the term "aheterocyclicthio(lower)alkyl" means saturated or unsaturated, monocyclicor polycyclic heterocyclic group containing at least one hetero-atomsuch as an oxygen, sulfur, nitrogen atom and the like. And, especiallypreferably heterocyclic group may be heterocyclic group such as

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), dihydrotriazinyl, etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolidinyl, imidazolinyl, piperidino,piperazinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatom(s), for example, indolyl, isoindolyl, indolizynyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl,tetrazolopyridazinyl, dihydrotriazolopyridazinyl, etc.;

unsaturated 3-to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl,isoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.) etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl,etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.;

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl,thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.), etc.;

saturated 3 to 8-membered heteromonocyclic group containing 1 to 2sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl,etc.;

unsaturated 3 to 8-membered heteromonocyclic group contaning a sulphuratom, for example, thienyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc. and the like;

wherein said heterocyclic group may be substituted with 1 to 3 suitablesubstituent(s) such as lower alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl,etc.); lower alkylthio (e.g., methylthio, ethylthio, propylthio, etc.);lower alkenyl (e.g., vinyl, allyl, butenyl, etc.); lower allkenylthio(e.g., vinylthio, allylthio, butenylthio, etc.); hydroxy; aryl (e.g.,phenyl, tolyl, etc.); halogen (e.g., chlorine, bromine, iodine orfluorine); amino; di(lower)alkylamino(lower)alkyl (e.g.,dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,diethylaminopropyl, diethylaminobutyl, etc.); carboxy(lower)alkyl (e.g.,carboxymethyl, carboxyethyl, carboxypropyl, etc.); esterifiedcarboxy(lower)alkyl wherein the esterified carboxy moiety is exemplifiedabove; amino(lower)alkyl (e.g., aminomethyl, aminoethyl, aminopropyl,1-aminomethylethyl, aminobutyl, aminohexyl, etc.), protectedamino(lower)alkyl wherein the protected amino and lower alkyl moietiesare each as exemplified above, preferably loweralkoxycarbonylamino(lower)alkyl (e.g., methoxycarbonylaminomethyl,ethoxycarbonylaminomethyl, t-butoxycarbonylaminomethyl,t-butoxycarbonylaminopropyl, etc.) or lower alkanoylamino(lower)alkyl(e.g., acetylaminomethyl, acetylaminoethyl, acetylaminopropyl,1-acetylaminomethylethyl, etc.); carboxy; oxo; esterified carboxy asexemplified above, preferably lower alkoxycarbonyl; loweralkoxy(lower)alkyl (e.g., methoxymethyl, methoxyethyl, methoxypropyl,ethoxymethyl, ethoxyethyl, etc.); hydroxy(lower)alkyl(e.g.,hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.); loweralkylthio(lower)alkyl (e.g., methylthiomethyl, methylthioethyl,methylthiopropyl, ethylthiomethyl, etc.); sulfo(lower)alkyl (e.g.,sulfomethyl, sulfoethyl, sulfopropyl, sulfobutyl, etc.);acyl(lower)alkyl wherein the acyl and lower alkyl moieties are each asexemplified above, preferably lower alkanesulfonyl(lower)alkyl (e.g.,mesylmethyl, mesylethyl, ethanesulfonylmethyl, etc.);acylamino(lower)alkyl wherein the acyl and lower alkyl moieties are eachas exemplified above, preferably lower alkanesulfonylamino(lower)alkyl(e.g., mesylaminomethyl, mesylaminoethyl, mesylaminopropyl,ethanesulfonylaminomethyl, etc.); carboxy(lower)alkylthio (e.g.,carboxymethylthio, carboxyethylthio, etc.); morpholino(lower)alkyl(e.g., morpholinomethyl, morpholinoethyl, morpholinopropyl, etc.);piperidino(lower)alkyl (e.g., piperidinomethyl, piperidinoethyl,piperidinopropyl, etc.); piperazinyl(lower)alkyl which may besubstituted with lower alkyl (e.g., 4-methyl-1-piperazinylpropyl, etc.);or the like.

Suitable substituent(s) on pyridinium(lower)alkyl, pyridine andpyridinium may be carbamoyl, lower alkanoyl as stated above,hydroxy(lower)alkyl(e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl,etc.), carboxy(lower)alkyl(e.g., carboxymethyl, carboxyethyl, etc.),.hydroxyiminomethyl, or the like.

Suitable substituent(s) on thiazolium(lower)alkyl, thiazole andthiazolium may include lower alkyl and hydroxy(lower)alkyl.

Suitable halogen can be referred to the ones as exemplified above.

Suitable lower alkylene may include straight or branched bivalentaliphatic hydrocarbon residue having 1 to 6 carbon atom(s), such asmethylene, ethylene, methylethylene, propylene, trimethylene,2-methyltrimethylene or the like, and preferably one having 1 to 4carbon atom(s), more preferably one having 1 to 2 carbon atom(s) and themost preferably one having 1 carbon atom.

Suitable protected amino(lower)alkyl and amino(lower)alkyl being thesubstituent of a heterocyclicthio(lower)alkyl for R^(4c) and R^(4d) andprotected amino(lower)alkyl and amino(lower)alkyl for R^(2b) and R^(2c)and protected carboxy(lower)alkyl and carboxy(lower)alkyl for R^(2d) andR^(2e) can be referred to the ones as exemplified above.

Suitable protective group of hydroxy may include aforesaid acyl,ar(lower)alkyl, and the like.

Suitable R^(4a) may include aforesaid acyloxy, halogen, azido and thelike.

Suitable R⁸ may be ester moiety as exemplified for protected carboxy.

Suitable protective group of carboxy may be referred to the onesexemplified as aforementioned ester moiety in the esterified carboxygroup. Preferable example of protective group of carboxy may be loweralkyl as mentioned above.

Suitable alkali metal may include sodium, potassium, lithium, etc.

Suitable reactive derivative of hydroxy for X may include an acidresidue such as aforesaid halogen or the like.

Suitable amino having a protective group for R⁹ may include phthalimido,succinimido, ethoxycarbonylamino and the like, and preferablyphthalimido.

Suitable ar(lower)alkyl may be preferably phenyl(lower)alkyl such asbenzyl, phenethyl, or the like.

Suitable (C₃ -C₆)alkyl in the terms "amino(C₃ -C₆)alkyl" and "protectedamino(C₃ -C₆)alkyl" may include alkyl having 3 to 6 carbon atoms, forexample, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or the like.

Suitable protected amino(lower)alkyl and amino(lower)alkyl for R^(2f)and R^(2g) and protected amino moiety in the term "protected amino(C₃-C₆)alkyl" can be referred to the ones as mentioned above.

Preferred embodiments of the object compound (I) are as follows.Preferred embodiment of R¹ is amino, acylamino (more preferably loweralkanoylamino) or di(lower)alkylamino(lower)alkylideneamino;

R² is hydrogen; aryl(more preferably phenyl); lower alkenyl; loweralkynyl; cyano(lower)alkyl; ar(lower)alkyl [more preferablyphenyl(lower)alkyl or triphenyl(lower)alkyl]; aryloxy(lower)alkyl [morepreferably phenoxy(lower)alkyl]; halo(lower)alkyl [more preferablytrihalo(lower)alkyl]; lower alkylthio(lower)alkyl; esterifiedcarboxy(lower)alkyl [more preferably lower alkoxycarbonyl(lower)alkyl];di(lower)alkylcarbamoyl(lower)alkyl; loweralkoxy(lower)alkoxy(lower)alkyl; lower alkanesulfonyl(lower)alkyl;acylamino(lower)alkyl[more preferably loweralkoxycarbonylamino(lower)alkyl]; amino(lower)alkyl;carboxy(lower)alkyl; cycloalkyl;cyclo(lower)alkenyl; aryl(morepreferably phenyl) substituted with halogen, nitro and lower alkoxy,halo(lower)alkyl or lower alkoxycarbonyl; thiolanyl substituted with 2oxo groups; ar(lower)alkyl substituted with carboxy or loweralkoxycarbonyl; cycloalkyl substituted with carboxy or loweralkoxycarbonyl; ar(lower)alkyl(preferably phenyl(lower)alkyl)substituted with amino(lower)alkyl or loweralkoxycarbonylamino(lower)alkyl; cycloalkyloxycarbonyl(lower)alkyl;ar(lower)alkoxycarbonyl(lower)alkyl;ar(lower)alkanoylamino(lower)alkylsubstituted with amino or lower alkoxycarbonylamino;cyclo(lower)alkyl(lower)alkanoylamino(lower)alkyl; tetrahydrofurylsubstituted with oxo group;

R³ is hydrogen or lower alkyl;

R⁴ is hydrogen; acyloxy(lower)alkyl [more preferably loweralkanoyloxy(lower)alkyl or carbamoyloxy(lower)alkyl, most preferablylower alkanoyloxymethyl or carbamoyloxymethyl]; acylthio(lower)alkyl[more preferably lower alkanoylthio(lower)alkyl, most preferably loweralkanoylthiomethyl]; tetrazolylthio(lower)alkyl (more preferablytetrazolylthiomethyl) which may be substituted with lower alkyl,loweralkenyl, lower alkoxy(lower)alkyl, lower alkylthio(lower)alkyl,hydroxy(lower)alkyl, amino(lower)alkyl, loweralkoxycarbonylamino(lower)alkyl, lower alkanoylamino(lower)alkyl,di(lower)alkylamino(lower)alkyl, sulfo(lower)alkyl, carboxy(lower)alkyl,aryl(more preferably phenyl), lower alkoxycarbonyl(lower)alkyl,morpholino(lower)alkyl, piperidino(lower)alkyl orpiperazinyl(lower)alkyl substituted with lower alkyl;thiazolium(lower)alkyl substituted with lower alkyl andhydroxy(lower)alkyl; thiadiazolylthio(lower)alkyl (more preferablythiadiazolylthiomethyl) which may be substituted with lower alkyl, loweralkoxy(lower)alkyl, lower alkylthio(lower)alkyl, lower alkenylthio,carboxy, lower alkoxycarbonyl, hydroxy(lower)alkyl, amino(lower)alkyl,lower alkoxycarbonylamino(lower)alkyl, lower alkanesulfonyl(lower)alkyl,lower alkanesulfonylamino(lower)alkyl or carboxy(lower)alkylthio;pyridinium(lower)alkyl which may be substituted with carbamoyl, loweralkanoyl, hydroxy(lower)alkyl, carboxy(lower)alkyl orhydroxyiminomethyl; lower alkyl; halogen; hydroxy;dihydrotriazolopyridazinylthio(lower)alkyl(more preferablydihydrotriazolopyridazinylthiomethyl) substituted with oxo andcarboxy(lower)alkyl; dihydrotriazinylthio(lower)alkyl(more preferablydihydrotriazinylthiomethyl) substituted with oxo, hydroxy and loweralkyl; or tetrazolopyridazinylthio(lower)alkyl (more preferablytetrazolopyridazinylthiomethyl); and R⁵ is carboxy,phenyl(lower)alkoxycarbonyl substituted with nitro, loweralkanoyloxy(lower)alkoxycarbonyl, loweralkoxycarbonyloxy(lower)alkoxycarbonyl which may be substituted withazido, phthalidyloxycarbonyl or aroyl(preferablybenzoyl)oxy(lower)alkoxycarbonyl; wherein R⁵ is COO⁻ when R⁴ ispyridinium(lower)alkyl which may be substituted with carbamoyl, loweralkanoyl, hydroxy(lower)alkyl, carboxy(lower)alkyl orhydroxyiminomethyl, or thiazolium(lower)alkyl substituted with loweralkyl and hydroxy(lower)alkyl.

The processes for preparing the object compounds are explained indetails in the following.

PROCESS 1

The object compound (I) can be prepared by reacting the compound (II) orits reactive derivative at the amino group or a salt thereof with thecompound (III) or its reactive derivative at the carboxy group or a saltthereof.

Suitable reactive derivative at the amino group of the compound (II) mayinclude conventional reactive derivative used in amidation, for example,Schiff's base type imino or its tautomeric enamine type isomer formed bythe reaction of the compound (II) with a carbonyl compound; a silylderivative formed by the reaction of the compound (II) with a silylcompound such as bis (trimethylsilyl)acetamide, trimethylsilylacetamideor the like; a derivative formed by reaction of the compound (II) withphosphorus trichloride or phosgene, and the like.

Suitable salt of the compound (II) may include an acid addition saltsuch as an organic acid salt (e.g., acetate, maleate, tartrate,benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metalsalt (e.g., sodium salt, potassium salt, calcium salt, magnesium salt,etc.); ammonium salt; an organic amine salt (e.g., triethylamine salt,dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. The suitable example may be an acidchloride; an acid azide; a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, acetic acid or trichloroacetic acid, etc.) oraromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acidanhydride; an activated amide with imidazole, dimethylpyrazole, triazoleor tetrazole; or an activated ester (e.g., cyanomethyl ester,methoxymethyl ester, dimethyliminomethyl [(CH₃)₂ N⁺ ═CH--] ester, vinylester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester,phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester,p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridylester, piperidyl ester, 8-quinolyl thioester, or an ester withN,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactivederivatives can be optionally selected from them according to the kindof the compound (III) to be used.

The salts of the compound (III) may be salts with an inorganic base suchas an alkali metal salts (e.g., sodium or potassium salt), or analkaline earth metal salt (e.g., calcium or magnesium salt), a salt withan organic base such as trimethylamine, triethylamine, pyridine, a saltwith an acid (e.g., hydrochloric acid or hydrobromic acid) or the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence to the reaction. Among these solvents,hydrophilic solvents may be used in a mixture with water.

When the compound (III) is used in free acid form of its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide;N,N-diethylcarbodiimide; N,N-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis(2-methylimidazole);pentamethylene-ketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene; ethyl polyphosphate;isopropyl polyphosphate; diethyl phosphorochloridite; phosphorusoxychloride; phosphorus trichloride; phosphorus pentachloride; thionylchloride; oxalyl chloride; triphenylphosphine;N-ethyl-7-hydroxybenzisoxazolium fluoroborate;N-ethyl-5-phenylisoxazolium-3'-sulfonate;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent, for example (chloromethylene) dimethylammoniumchloride produced by the reaction of dimethylformamide with thionylchloride or phosgene, a compound produced by the reaction ofdimethylformamide with phosphorus oxychloride, etc.; or the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal hydroxide, an alkali metalbicarbonate, alkali metal carbonate, alkali metal acetate,tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline as exemplifiedbelow, or the like. When the base or the condensing agent is in liquid,it can be used also as a solvent. The reaction temperature is notcritical, and the reaction is usually carried out under cooling or atambient temperature.

In the present invention, a syn-isomer of the object compound (I) can beobtained preferably by conducting the reaction of the compound (II) witha syn-isomer of the starting compound (III).

In the present reaction, amino group for R¹ in the compound (III) may beconverted into a protected amino group to give the compound (I) whereinR¹ is a protected amino, and acyl for R² may be converted into hydrogenin the course of the reaction according to reaction conditions, andthese cases are included within the scope of the present invention.

PROCESS 2

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to elimination reaction of theprotective group of carboxy.

Suitable salt of the compound (Ia) can be referred to the acid additionsalt exemplified for the compound (II).

The present reaction is carried out in accordance with a conventionalmethod such as hydrolysis, reduction or the like.

In case that the protective group is an ester, the protective group canbe eliminated by hydrolysis. Hydrolysis is preferably carried out in thepresence of a base or an acid. Suitable base may include an inorganicbase and an organic base such as an alkali metal (e.g., sodium,potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium,etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine(e.g., trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]none-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]undecene-7, or the like. Suitable acid mayinclude an organic acid (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.) and an inorganic acid (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence to the reaction. A liquidbase or acid can be also used as the solvent. The reaction temperatureis not critical and the reaction is usually carried out under cooling towarming.

Reduction can be applied preferably for elimination of the protectivegroup such as 4-nitrobenzyl, 2-iodoethyl, 2,2,2-trichloroethyl, or thelike. The reduction method applicable for the elimination reaction mayinclude, for example, reduction by using a combination of a metal (e.g.,zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g., chromouschloride, chromous acetate, etc.) and an organic or inorganic acid(e.g., acetic acid, propionic acid, hydrochloric acid, etc.); andconventional catalytic reduction in the presence of a conventionalmetallic catalyst (e.g., palladium-carbon, etc.).

PROCESS 3

The object compound (Id) or a salt thereof can be prepared by reactingthe compound (Ic) or a salt thereof with the compound (IV) or itsreactive derivative.

Suitable salt of the compound (Ic) can be referred to the onesexemplified for the compound (II).

Suitable reactive derivative of the compound (IV) may include a metalsalt such as an alkali metal salt (e.g., sodium salt, potassium salt,etc.) or the like.

The present reaction may be carried out in a solvent such as water,phosphate buffer, acetone, chloroform, nitrobenzene, methylene chloride,ethylene chloride, dimethylformamide, methanol, ethanol, ether,tetrahydrofuran, dimethylsulfoxide, or any other organic solvent whichdoes not adversely affect the reaction, preferably in ones having strongpolarities. Among the solvents, hydrophilic solvents may be used in amixture with water. The reaction is preferably carried out in aroundneutral medium. When the compound (Ic) or the compound (IV) is used in afree form, the reaction is preferably conducted in the presence of abase, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkali metal bicarbonate, organic base such astrialkylamine, and the like. The reaction temperature is not critical,and the reaction is usually carried out at ambient temperature, underwarming or under slightly heating.

The present invention includes, within its scope, the case thatprotected carboxy group is converted to free carboxy group during thecourse of the reaction.

PROCESS 4

The object compound (If) or a salt thereof can be prepared by subjectingthe compound (Ie) or a salt thereof to elimination reaction of theprotective group of amino.

Suitable salt of the compound (Ie) may include a metal salt, ammoniumsalt, an organic amine salt and the like as aforementioned.

The present elimination reaction is carried out in accordance with aconventional method such as hydrolysis; reduction; a method by reactingthe compound (Ie) wherein the pretective group is acyl group withiminohalogenating agent and then with iminoetherifying agent, and, ifnecessary, subjecting the resulting compound to hydrolysis; or the like.The hydrolysis may include a method using an acid or base or hydrazineand the like. These methods may be selected depending on the kind of theprotective groups to be eliminated.

Among these methods, hydrolysis using an acid is one of the common andpreferable method for eliminating the protective group such assubstituted or unsubstituted alkoxycarbonyl (e.g., t-pentyloxycarbonyl,t-butoxycarbonyl, etc.), alkanoyl (e.g., formyl, etc.),cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl(e.g., benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.),substituted phenylthio, substituted aralkylidene, substitutedalkylidene, substituted cycloalkylidene, ar(lower)alkyl (e.g., benzyl,trityl, etc.) or the like.

Suitable acid may include an organic or an inorganic acid, for example,formic acid, trifluoroacetic acid, benzenesulfuric acid,p-toluenesulfonic acid, hydrochloric acid and the like, and preferableacid is, for example, formic acid, trifluoroacetic acid, hydrochloricacid, etc. The acid suitable for the reaction can be selected accordingto the kind of protective group to be eliminated. When the eliminationreaction is conducted with the acid, it can be carried out in thepresence or absence of a solvent. Suitable solvent may include aconventional organic solvent, water or a mixture thereof. Whentrifluoroacetic acid is used, the elimination reaction may preferably becarried out in the presence of anisole.

The hydrolysis using hydrazine is commonly applied for eliminating theprotective group, for example, succinyl or phthaloyl.

The hydrolysis with a base is preferably applied for eliminating acylgroup, for example, haloalkanoyl (e.g., dichloroacetyl, trifluoroacetyl,etc.) etc. Suitable base may include, for example, an inorganic basesuch as alkali metal hydroxide (e.g., sodium hydroxide, potassiumhydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesiumhydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g.,sodium carbonate, potassium carbonate, etc.), alkaline earth metalcarbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkalimetal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate,etc.), alkali metal acetate (e.g., sodium acetate, potassium acetate,etc.), alkaline earth metal phosphate (e.g., magnesium phosphate,calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g.,disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), orthe like, and an organic base such as trialkylamine (e.g.,trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine,N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-ene,1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5-or thelike. The hydrolysis using a base is often carried out in water, aconventional organic solvent or a mixture thereof.

Among the protective group, the acyl group can be generally eliminatedby hydrolysis as mentioned above or by the other conventionalhydrolysis. In case that the acyl group is halogensubstituted-alkoxycarbonyl or 8-quinolyloxycarbonyl, they are eliminatedby treating with a heavy metal such as copper, zinc or the like.

The reductive elimination is generally applied for eliminating theprotective group, for example, haloalkoxycarbonyl (e.g.,trichloroethoxycarbonyl etc.), substituted or unsubstitutedaralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyletc.), 2-pyridylmethoxycarbonyl, etc. Suitable reduction may include,for example, reduction with an alkali metal borohydride (e.g., sodiumborohydride, etc.) and the like.

The reaction temperature is not critical and may be suitably selected inaccordance with the kind of the protective group of the amino group andthe elimination method as mentioned above, and the present reaction ispreferably carried out under a mild condition such as under cooling, atambient temperature or slightly elevated temperature.

The present reaction includes, within its scope, the cases that theprotected carboxy group for R² and/or R³ is transformed into the freecarboxy group in the course of the elimination reaction as mentionedabove or in the post-treatment of the reaction mixture or reactionproduct.

PROCESS 5

The object compound (Ij) or a salt thereof can be prepared by subjectingthe compound (Ii) or a salt thereof to elimination reaction of theprotective group of amino.

Suitable salt of the compound (Ii) can be referred to the ones asexemplified for the compound (II).

The present elimination reaction can be carried out according tosubstantially the same manner as that of Process 4.

The present reaction includes, within its scope, the case that protectedamino(lower)alkyl being the substituent on heterocyclicthio(lower)alkylfor R⁴ is transformed into amino(lower)alkyl.

PROCESS 6

The object compound (II) or a salt thereof can be prepared by subjectingthe compound (Ik) or a salt thereof to elimination reaction of theprotective group of carboxy.

Suitable salt of the compound (Ik) can be referred to the ones asexemplified for the compound (II).

The present elimination reaction can be carried out according tosubstantially the same manner as that of

PROCESS 2

The present reaction includes, within its scope, the case that protectedamino(lower)alkyl being the substituent on heterocyclicthio(lower)alkylfor R⁴ is transformed into amino(lower)alkyl.

PROCESS 7

The object compound (In) can be prepared by subjecting the compound (Im)or a salt thereof to esterification.

Suitable salt of the compound (Im) can be referred to the ones asexemplified for the compound (II).

The present reaction may be carried out by reacting the compound (Im) ora salt thereof with esterifying agent.

Suitable esterifying agent may be a compound of the formula:

    X--R.sup.8                                                 (XVII)

wherein R⁸ and X are each as defined above.

The present reaction is usually carried out in a solvent such asdimethylformamide, pyridine, hexamethylphosphoric triamide or any othersolvent which does not adversely affect the reaction.

In case that the compound (Im) is used in a form of free acid, thereaction is preferably carried out in the presence of a base asmentioned above.

The reaction temperature is not critical and the reaction is preferablycarried out under cooling, at ambient temperature or under warming.

PROCESS 8

The object compound (Ih) or a salt thereof can be prepared by subjectingthe compound (Ig) or a salt thereof to elimination reaction of theprotective group of hydroxy.

Suitable salt of the compound (Ig) can be referred to the ones asexemplified for the compound (II).

The present elimination reaction can be carried out according tosubstantially the same manner as that of Process 4.

PROCESS 9

The object compound (I_(p)) or a salt thereof can be prepared bysubjecting the compound (Io) or a salt thereof to dehydration reaction.

The present invention is preferably carried out by reacting the compound(Ic) or a salt thereof with dehydrating agent.

Suitable dehydrating agent may include an acid such as alkanoic acidwhich may be substituted with halogen (e.g., pivalic acid,trifluoroacetic acid, etc.), arenesulfonic acid(e.g., toluenesulfonicacid, etc.) or the like; or its halide(e.g., trifluoroacetyl chloride,tosylchloride, pivaloylchloride, phosphorus oxychloride, etc.); or itssymmetrical acid anhydride; unsymmetrical mixed acid anhydride; areactive derivative of diketene or the like; florisil; Girard reagent T;ethyl(carboxysulfamoyl); a ylide compound (e.g. an intramolecular saltof triethylammonium hydroxide, etc.); and the like.

The present reaction may preferably be carried out in the presence of abase.

The preferable base includes an inorganic base such as metal hydroxide(e.g. sodium hydroxide, potassium hydroxide, etc.), metal carbonate(e.g. sodium carbonate, potassium carbonate, magnesium carbonate, etc.),metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate,etc.), organic base such as tertiary amine (e.g. trimethyl amine,triethyl amine, pyridine, etc.), alkali metal alkoxide (e.g. sodiummethoxide; sodium ethoxide, etc.)

The reaction is usually carried out in a conventional solvent such as analcohol, tetrahydrofuran, dimethylformamide, chloroform, methylene,chloride or any other solvent which does not adversely influence thereaction, under cooling or at an ambient or somewhat elevatedtemperature.

PROCESS 10

The object compound (Ir) or a salt thereof can be prepared by subjectingthe compound (Iq) or a salt thereof to introduction reaction of theprotective group of amino.

Suitable salt of the compound (Iq) can be referred to the ones asexemplified for the compound (II).

The present reaction can be carried out according to substantially thesame manner as that of Process 1.

The preparation for preparing the starting compound (III) are explainedbelow in detail.

PREPARATION (1)

The compound (VII) can be prepared by reacting the compound (V) or asalt thereof with halogenating agent and the compound (VI).

Suitable halogenating agent to be used in the present reaction mayinclude bromine, chlorine and the like.

The present reaction is preferably carried out in the presence of a basesuch as an inorganic base or an organic base, for example, alkali metalcarbonate, alkali metal alkoxide, trialkylamine or the like. The presentreaction is usually carried out in a solvent such as an alcohol (e.g.,methanol, ethanol, etc.) or any other solvent which does not adverselyaffect the reaction. The reaction temperature is not critical and thereaction is usually carried out under cooling or at ambient temperature.In this reaction, R⁶ of the compound (V) may be converted into otherprotective group of carboxy according to reaction conditions and kindsof the protective group and it is included within the scope of thepresent invention.

PREPARATION (2)

The compound (VIII) can be prepared by subjecting the compound (VII) tointroduction reaction of the protective group of amino.

The present process can be carried out in a conventional manner and whenthe protective group of amino to be introduced into the amino group isacyl, the reaction can be carried out in substantially the same manneras that of Process 1. Accordingly, the detailed explanation therefor isto be referred to said Process 1.

PREPARATION (3)

The compound (X) can be prepared by reacting the compound (VIII) withthe compound (IX). This process is usually carried out in the presenceof base such as an alkali metal hydride (e.g., sodium hydride, potassiumhydride, etc.), an alkaline earth metal hydride (e.g., calcium hydride,etc.) and the like, and usually carried out in a solvent such asdimethylformamide or any other solvent which does not adversely affectthe reaction. The reaction temperature is not critical and the reactionis usually carried out under cooling, at ambient temperature or underwarming.

PREPARATION (4)

The compound (XI) can be prepared by reacting the compound (X) with anacid and/or acid anhydride such as acetic acid and/or acetic anhydride.The reaction of this process can preferably be carried out in thepresence of alkali metal perhaloate (e.g., sodium perchlorate, sodiumperiodate, potassium perchlorate, etc.), alkaline earth metalperchlorate (e.g., magnesium perchlorate, calcium perchlorate, etc.) andthe like, and an acid such as an organic acid (e.g., formic acid, etc.)or an inorganic acid (e.g., hydrochloric acid).

The reaction temperature is not critical and the reaction is usuallycarried out under warming.

PREPARATIONS (5) AND (7)

The preparation (5) and (7) can be carried out in a conventional manneras shown in Process 2 or 4.

In the preparation (5), according to reaction conditions, there may beobtained the product having R^(1a) (XIa) or the product having aminoinstead of R^(1a) (XIb) and they are subsequently reacted with thecompound (XII) or a salt thereof to give the compound (IIIa) or (IIIb),respectively, as shown in Preparation (6).

PREPARATION (6)

Suitable salt of the compound (XII) is a conventional acid salt such asan inorganic acid salt (e.g., hydrochloride, etc.) and an organic acidsalt (e.g., p-toluenesulfonic acid salt, etc.). When salt of saidcompound (XII) is used in this process, the reaction is usually carriedout in the presence of a base such as an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, etc.). The reaction is usuallycarried out in a solvent such as water, an alcohol (e.g., methanol,ethanol, etc.) or any other solvent which does not adversely affect thereaction. The reaction temperature is not critical and the reaction isusually carried out at ambient temperature.

PREPARATION (8)

The compound (IIId) can be prepared by subjecting the compound (IIIc) tointroduction reaction of the protective group of hydroxy group.

The present process can be carried out in a conventional manner and whenthe protective group to be introduced into the hydroxy group is acyl,the reaction can be carried out in substantially the same manner as thatof Process 1.

In case that the protective group to be introduced is ar(lower)alkyl,the present reaction is carried out by reacting the compound (IIIc) withthe compound of the formula:

    R.sup.2f --Y                                               (XVIII)

wherein R^(2f) is ar(lower)alkyl and Y is an acid residue.

Suitable acid residue may include a residue of an acid such as aninorganic acid, for example, hydrohalogenic acid (e.g., hydrochloricacid, hydrobromic acid, etc.), sulfuric acid or the like, or an organicacid, for example, lower alkanesulfonic acid (e.g., methanesulfonicacid, ethanesulfonic acid, etc.), arenesulfonic acid (e.g.,benzenesulfonic acid, p-toluenesulfonic acid, etc.) or the like. Thepresent reaction is preferably carried out in the presence of a base asmentioned above and usually carried out in a solvent such asdimethylformamide or the like. The reaction temperature is not criticaland the reaction is usually carried out under cooling, at ambienttemperature or under warming.

PREPARATION 9

The compound (XV) can be prepared by reacting a compound (XIII) with acompound (XIV).

The reaction is preferably carried out in the presence of a base asexemplified in Process 1 in case that X is an acid residue and in thepresence of a condensing agent, for example, one formed bytriphenylphosphine and diethyl azoformate in case that X is hydroxy,respectively.

The reaction is usually carried out in a solvent such as acetonitrile,dimethylformamide, tetrahydrofuran or any other solvents which do notadversely influence the reaction. The reaction temperature is notcritical and the reaction is usually carried out from cooling to heatingaround a boiling point of the solvent used.

PREPARATION 10

The compound (XVI) or a salt thereof can be prepared by subjecting acompound (XV) to elimination reaction of the amino protective group.

This elimination reaction of the amino protective group of the compound(XV) can be carried out in a similar manner to that of aforementionedProcess 4

Suitable solvents include water, ethanol, chloroform, diethyl ether andthe like. The reaction temperature is not critical and the reaction isusually carried out under warming or heating. The present reactionincludes, within its scope, the case that protected amino group in R² isconverted into free amino group.

PREPARATION 11

The compound (XX) or a salt thereof can be prepared by subjecting thecompound (XIX) or a salt thereof to introduction reaction of theprotective group of amino.

The present reaction can be carried out according to substantially thesame manner as that of Process 1.

In case that protective group to be introduced is lower alkoxycarbonylgroup, this reaction is preferably carried out by reacting the compound(XIX) with a compound of the formula; ##STR12## wherein R¹² is loweralkoxycarbonyl and R¹³ is aryl.

PREPARATION 12

The compound (XXII) or a salt thereof can be prepared by subjecting thecompound (XXI) or a salt thereof to introduction reaction of thesubstituent on hydroxy group.

In case that substituent to be introduced is aryl which may besubstituted with suitable substituent(s), the present reaction isconducted by reacting the compound (XXI) or a salt thereof with acompound of the formula:

    R.sup.2i --X.sup.2⊕ --R.sup.2i Y.sup.⊖         (XXX)

wherein R^(2i) is aryl which may be substituted with suitablesubsfituent(s), X² is halogen and Y is an acid residue.

Suitable acid residue may include halogen, toluenesulfonyloxy, residueof sulfuric acid and the like.

The present reaction is usually carried out in a solvent such asalcohol(e.g., methanol, ethanol, etc.), water, mixed solvent thereof, orany other solvent which does not adversely affect the reaction, andpreferably carried out in the presence of a base.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling, at ambient temperature or under warming.

In case that substituent to be introduced is cycloalkyl which may besubstituted with suitable substituent(s), the reaction is carried out byreacting the compound (XXI) or a salt thereof with a compound of theformula:

    R.sup.2j --Y                                               (XXXI)

wherein R^(2j) is cycloalkyl which may be substituted with suitablesubstituent(s) and Y is as defined above.

This reaction is carried out according to substantially the same manneras that of Preparation 8.

PREPARATION 13

The compound (XXIV) or a salt thereof can be prepared by subjecting thecompound (XXIII) or a salt thereof to cyclization reaction.

The present reaction is usually carried out in a solvent such as alcohol(e.g., methanol, ethanol, etc.) or the like.

This reaction is carried out in the presence of dehydrating agent suchas magnesium sulfate, acid anhydride (e.g., acetic anhydride, etc.) orthe like.

The reaction temperature is not critical and it is usually carried outunder warming or heating or at ambient temperature.

PREPARATION 14

The compound (XXVI) or a salt thereof can be prepared by reacting thecompound (XXV) with HN₃ or a salt thereof.

Suitable salt of HN₃ may be alkali metal salt.

The reaction is usually carried out in a solvent such as water, dioxane,mixed solvent thereof or any other one which does not adversely affectthe reaction.

The reaction temperature is not critical and the reaction is usuallycarried out under heating.

PREPARATION 15

The compound (XXVII) or a salt thereof can be prepared by subjecting thecompound (XXVI) or a salt thereof to elimination reaction of theprotective group of amino.

The present reaction is carried out according to substantially the samemanner as that of Process 4.

PREPARATION 16

The compound (XXVIII) or a salt thereof can be prepared by subjectingthe compound (XXVII) or a salt thereof to introduction reaction of theprotective group of amino.

The present reaction is carried out according to substantially the samemanner as that of Preparation 11.

In the aforementioned reactions and/or in the post treatment of thereactions of the present invention, the aforementioned tautomericisomers may occasionally be transformed into the other tautomericisomers and such case is also included in the scope of the presentinvention.

In case that the object compound (I) is obtained in a form of the freeacid at 4 position and/or in case that the object compound (I) has freeamino group, it may be optionally transformed into its pharmaceuticallyacceptable salt as aforementioned by a conventional method.

The object compound (I) and pharmaceutically acceptable salt thereof ofthe present invention are all novel compounds which exhibit highantibacterial activity, inhibiting the growth of a wide variety ofpathogenic microorganisms including Gram-positive and Gram-negativebacteria and are useful as antibacterial agents.

Now, in order to show the utility of the object compound (I), withregard to some representative compounds of this invention, the test dataon the in vitro anti-bacterial activity are shown in the following.

Test Compounds

(1)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer)

(2)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(3)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer)

(4)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(5)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(6)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(7)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(8)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(9)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(10)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(11)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer)

(12)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer)

(13)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer)

(14)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer)

(15)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer)

Test Method

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (HI-agar) containing graded concentrations of testcompounds, and minimal inhibitory concentration (MIC) was expressed interms of μg/ml. after incubation at 37° C. for 20 hours.

    __________________________________________________________________________    Test Results                                                                          MIC (μg/ml)                                                        Test    Test Compound                                                         Bacteria                                                                              (1)                                                                              (2)                                                                              (3)                                                                              (4)                                                                              (5)                                                                              (6)                                                                              (7)                                                                              (8)                                                                              (9)                                                                              (10)                                                                             (11)                                                                             (12)                                                                             (13)                                                                             (14)                                                                             (15)                        __________________________________________________________________________    E. coli NIHJ                                                                          0.39                                                                             0.78                                                                             0.39                                                                             0.78                                                                             3.13                                                                             3.13                                                                             0.20                                                                             0.10                                                                             0.20                                                                             0.78                                                                             1.56                                                                             0.78                                                                             1.56                                                                             0.78                                                                             0.78                        JC - 2                                                                        Kl. pneumoniae                                                                        0.78                                                                             3.13                                                                             0.78                                                                             1.56                                                                             3.13                                                                             3.13                                                                             1.56                                                                             0.10                                                                             0.20                                                                             1.56                                                                             3.13                                                                             1.56                                                                             1.56                                                                             6.25                                                                             1.56                        12                                                                            Pr. vulgaris                                                                          0.39                                                                             3.13                                                                             0.39                                                                             1.56                                                                             3.13                                                                             3.13                                                                             0.78                                                                             0.10                                                                             0.20                                                                             1.56                                                                             3.13                                                                             3.13                                                                             3.13                                                                             6.25                                                                             3.13                        Ps. aeruginosa                                                                        3.13                                                                             1.56                                                                             1.56                                                                             3.13                                                                             3.13                                                                             3.13                                                                             3.13                                                                             1.56                                                                             3.13                                                                             12.5                                                                             6.25                                                                             6.25                                                                             6.25                                                                             3.13                                                                             3.13                        NCTC-10490                                                                    __________________________________________________________________________

For therapeutic administration, the object compound (I) of the presentinvention is used in the form of conventional pharmaceutical preparationwhich contains said compounds, as an active ingredient, in admixturewith a pharmaceutically acceptable carriers such as an organic orinorganic solid or liquid excipient which is suitable for oral,parenteral or external administration. The pharmaceutical preparationsmay be in solid from such as capsule, tablet, dragee, ointment orsuppository, or in liquid form such as solution, suspension, oremulsion. If needed, there may be included in the above preparationsauxiliary substances, stabilizing agents, wetting or emulsifying agents,buffers and the other commonly used additives.

While the dosage of the compounds may vary from and also depend upon theage, conditions of the patient, a kind of disease, a kind of thecompound (I) to be applied, etc., an average single dose of about 50mg., 100 mg., 250 mg, and 500 mg. of the object compound (I) of thepresent invention has proved to be effective in treating diseasesinfected by pathogenic bacteria.

In general, daily dose between 5 mg. and about 3,000 mg. or even moremay be administered to a patient.

The following Preparations and Examples are given for the purpose ofillustrating the present invention:

PREPARATION 1

(1) A mixture of N-hydroxyphthalimide (8.15 g), triethylamine (5.05 g),N,N-dimethylformamide (60 ml) and 1-bromo-2-cyclohexene (8.05 g) wasstirred for 3.5 hours at room temperature. The reaction mixture waspoured into water (300 ml). The precipitated crystals were collected byfiltration, washed successively with water and n-hexane and then driedto give N-(2-cyclohexen-1-yloxy)phthalimide (9.8 g). mp 87° C.

I.R. (Nujol): 1770, 1720, 1610 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.17 (6H, m), 4.60-4.77 (1H, m), 5.73-6.27(2H, m), 7.90 (4H, s)

(2) A mixture of N-hydroxyphthalimide (52.16 g), bromocycloheptane(62.41 g), dimethylsulfoxide (385 ml) and potassium carbonate (44.16 g)were stirred for 74 hours at 70° C. The reaction mixture was cooledunder ice-cooling and added to ice-water (1.5 l). The precipitates werecollected by filtration, washed with ice-water (×2) and then dried togive N-(cycloheptyloxy)phthalimide (63 g), mp 110° to 112° C.

N.M.R. (d₆ -DMSO, δ): 1.57 (8H, m), 1.90 (4H, m), 4.20 (1H, m), 7.93(4H, s).

(3) A mixture of N-hydroxyphthalimide (58.2 g), 1-chloro-2-cyclopentene(36.9 g), triethylamine (53.9 g) in acetonitrile (370 ml) was treated insimilar manners to those of Preparations 1-(1) and 1-(2) to giveN-(2-cyclopenten-1-yloxy)phthalimide (56.5 g)

I.R. (Nujol): 1780, 1730, 1610 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 7.92 (4H, s), 6.28 (1H, m), 6.00 (1H, m), 5.42(1H, m), 2.9-1.98 (4H, m)

PREPARATION 2

A mixture of N-(cycloheptyloxy)phthalimide (2.59 g), hydrazine hydrate(0.45 g) in ethanol (12 ml) was refluxed for 5 minutes.

The reaction mixture was cooled and filtered to give the filtratecontaining cycloheptyloxyamine.

PREPARATION 3

(1) A mixture of N-(2-cyclopenten-1-yloxy)phthalimide (22.9 g) andhydrazine hydrate (4.75 g) in ethanol (115 ml) was refluxed for 5minutes. The reaction mixture was filtered. The filtrate containing(2-cyclopenten-1-yl)oxyamine was added to a solution of sodium2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate (22.4 g) in water. Themixture was adjusted to pH 2 with 10% hydrochloric acid, stirred for 2hours and then concentrated. The concentrate was adjusted to pH 1 with10% hydrochloric acid. The precipitates were collected by filtration anddried to give2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (20.0 g), mp 150° C. (dec.).

I.R. (Nujol): 3400, 3100, 1720, 1690, 1540 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30(2H, m), 8.90 (1H, s)

(2) A mixture of N-(2-cyclohexen-1-yloxy)phthalimide (7.29 g), hydrazinehydrate (1.5 g) in ethanol (40 ml) was refluxed for 5 minutes. Thereaction mixture was cooled and filtered to give the filtrate containing(2-cyclohexen-1-yl)oxyamine (filtrate A). On the other hand, a mixtureof S-methyl 2-(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (6.93 g)in 1 N-aqueous solution of sodium hydroxide (90 ml) was stirred for 30minutes at room temperature. The reaction mixture containing sodium2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate was adjusted to pH 7with 10% hydrochloric acid and thereto was added the filtrate A and thenthe pH was adjusted to 3 with 10% hydrochloric acid. The mixture wasstirred for 3 hours at room temperature. The reaction mixture wasconcentrated and to the concentrate was added ethyl acetate. The mixturewas adjusted to pH 1 with 10% hydrochloric acid. The precipitates werecollected by filtration to give2-(2-cyclohexen-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.5 g). On the other hand, the ethyl acetate layerwas separated from the filtrate and evaporated. The residue wastriturated with diethyl ether to give the same object compound (1.5 g).Total yield: 4.0 g, mp 190° to 192° C. (dec.).

I.R. (Nujol): 3550, 3400, 3200, 2500, 1690, 1590, 1540 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.5-2.3 (6H, m), 4.73-5.0 (1H, m), 5.76-6.23 (2H,m), 8.97 (1H, s), 13.60 (1H, broad s)

(3) To a solution of sodium hydroxide (11.2 g) in water (140 ml) wasadded S-methyl 2-(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (27g) at 10° C. and the mixture was stirred for 30 minutes at 20° C. Thereaction mixture containing sodium2-(5-formamido-1,2,4-thiadiazol-3-yl)glyoxylate was cooled, adjusted topH 7 with 10% hydrochloric acid and thereto was added a solution ofcyclopentyloxyamine (15.3 g) in ethanol (150 ml). The mixture wasadjusted to pH 3 with 10% hydrochloric acid, and stirred for 1.5 hours.The reaction mixture was adjusted to pH 7 with an aqueous solution ofsodium bicarbonate and then evaporated to remove ethanol. The residuewas washed with ethyl acetate. To the aqueous layer was added ethylacetate and the mixture was adjusted to pH 1 with 10% hydrochloric acid.The precipitates were collected by filtration to give2-cyclopentyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (3.99 g). The filtrate was extracted with ethyl acetate andthe extract was dried over magnesium sulfate and then concentrated. Theprecipitates were collected by filtration and washed with diethyl etherto give the same object compound (8.1 g). Total yield: 12.09 g, mp 180°to 185° C. (dec.).

I.R. (Nujol): 3130, 3040, 2680, 2610, 2520, 1720, 1690, 1660, 1600, 1550cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33-2.10 (8H, m), 4.67-5.0 (1H, m), 8.88 (1H, s),13.50 (1H, s)

(4) The following compound was obtained according to similar manners tothose of Preparations 3(1) to 3(3).

2-Cycloheptyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer).

N.M.R. (d₆ -DMSO, δ): 1.50 (8H, m), 1.80 (4H, m), 4.37 (1H, m), 8.81(1H, s), 9.88 (1H, s)

PREPARATION 4

A mixture of2-(2-cyclopenten-1-yl)oxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (20.0 g) and 1 N aqueous solution of sodium hydroxide(200 ml) was stirred for an hour at 50° to 55° C. The reaction mixturewas cooled, adjusted to pH 7 with 10% hydrochloric acid and thereto wasadded ethyl acetate. The mixture was adjusted to pH 1 with 10%hydrochloric acid and extracted with ethyl acetate. The extract waswashed with a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate and evaporated. The residue was pulverized withdiisopropyl ether to give2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 150° C. (dec.).

I.R. (Nujol): 3300, 3150, 1710, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.80-2.50 (4H, m), 5.30-5.50 (1H, m), 5.83-6.30(2H, m), 8.20 (2H, s)

PREPARATION 5

The following compounds were obtained according to a similar manner tothat of Preparation 4.

(1)2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 173° C.

I.R. (Nujol): 3400, 3300, 3200, 1720, 1620, 1600, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.17 (6H, m), 4.53-4.83 (1H, m), 5.57-6.13(2H, m), 8.18 (2H, s)

(2) 2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3470, 3290, 3200, 2400, 1715, 1615, 1600, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.17-2.10 (8H, m), 4.60-4.97 (1H, m), 8.22 (2H, s)

(3) 2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp 116° to 119° C. (dec.).

I.R. (Nujol): 3250, 3200, 1650, 1600, 1520, 1400, 1260, 1150, 1000, 820,720 cm⁻¹

PREPARATION 6

(1) A solution of 4-(3-aminopropyl)morpholine (122.6 g) in dioxane (520ml) was added to a solution of 97% sodium hydroxide (35.1 g) in water(420 ml) under 0° C. and thereto was added dropwise carbon disulfide(64.71 g) over a period of 0.5 hour at 0° to 5° C. The mixture wasstirred for an hour at the same temperature and thereto was added methyliodide (120.65 g) over a period of 0.5 hour at 0° to 5° C. The resultingmixture was stirred for 2 hours at the same temperature. Theprecipitates were collected by filtration, washed with water (×2) anddried to give a pale yellow powder of4-[3-{N-methylthio(thiocarbonyl)amino}propyl]morpholine (174.55 g).

N.M.R. (d₆ -DMSO, δ): 1.73 (2H, m), 2.3 (6H, m), 2.48 (3H, s), 3.2-3.9(6H, m), 9.91 (1H, broad s)

(2) To a solution of4-[3-{N-methylthio(thiocarbonyl)amino}propyl]morpholine (152 g) indioxane (430 ml) was added a solution of sodium azide (42.25 g) in water(290 ml). The resulting mixture was refluxed for 2 hours. The reactionmixture was evaporated, adjusted to pH 8 and washed with diethyl ether.The aqueous layer was adjusted to pH 5 and cooled. The precipitates werecollected by filtration, washed with ice-water (×2) and then dried togive white crystals of 1-(3-morpholinopropyl)-1H-tetrazole-5-thiol (116g), mp 210° to 212° C. (dec.).

I.R. (Nujol): 3550, 3500, 2350, 1610, 1410, 1360, 1280, 1190, 1130,1090, 1050, 990, 880, 825, 785 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.14 (2H, m), 2.99 (2H, t, J=7 Hz), 3.09 (4H, m),3.79 (4H, m), 4.24 (2H, t, J=7 Hz)

PREPARATION 7

(1) The following compound was obtained according to a similar manner tothat of Preparation 6(1).1-[3-{N-Methylthio(thiocarbonyl)amino}propyl]piperidine, white powder,mp 74° to 76° C.

I.R. (Nujol): 3450, 3150, 1670, 1560, 1410, 1340, 1315, 1255, 1030,1000, 950, 880, 860, 800, 750 cm⁻¹

(2) The following compound was obtained according to a similar manner tothat of Preparation 6(2). 1-(3-Piperidinopropyl)-1H-tetrazole-5-thiol,mp 142° to 144° C. (dec.).

I.R. (Nujol): 3500, 3350, 2450, 1635, 1360, 1280, 1200, 1185, 1120,1100, 1085, 1070, 1000, 965, 950, 810 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.3-1.9 (6H, m), 2.20 (2H, m), 3.07 (2H, t, J=7Hz), 3.17 (4H, m), 4.24 (2H, t, J=7 Hz)

PREPARATION 8

(1) To a mixture of tetrabutylammonium bromide (3.22 g) in methylenechloride (300 ml) was added ethyl chloroformate (108.5 g) at -20° C. Tothe mixture was added a solution of sodium cyanide (49 g) in water (200ml) over a period of 15 minutes at -10° to -13° C. and the resultingmixture was stirred for a minute at -13° C. The organic layer wasseparated from the reaction mixture, dried over magnesium sulfate andallowed to warm to room temperature. The methylene chloride layer wasseparated by decantation and the insoluble material was washed withmethylene chloride. The combined methylene chloride layers (370 ml) weredistilled at atmospheric pressure to give a solution containing ethylcyanoformate (335 ml), bp 42° to 117° C.

(2) A solution of hydrogen chloride (32.5 g) in ethanol (34.5 g) wascooled at -10° C. and added to a solution obtained in Preparation 8(1)(335 ml) containing ethyl cyanoformate precooled to -10° C. Theresulting solution was stirred for 6 hours at -5° to 5° C., cooled to-10° C. and thereto was added methylene chloride (400 ml). To themixture were dropwise added a solution of triethylamine (85.8 g) inmethylene chloride (80 ml) and water (200 ml) at -5° to 0° C. Themethylene chloride layer was separated, washed with water (200 ml×2),dried over magnesium sulfate and evaporated to give the product (112 g)containing 78.8% of ethyl 2-imino-2-ethoxyacetate. This product waspurified by distillation (bp 80° to 88° C./40 mmHg) to give pureproduct.

(3) A mixture of ethyl 2-imino-2-ethoxyacetate (60 g) (purity 78.8%) andammonium chloride (17.4 g) in methanol (180 ml) was stirred for 3 hoursat room temperature and cooled to -15° to -10° C. To the resultingmixture containing 1-methoxycarbonylformamidine hydrochloride weredropwise added bromine (51.2 g) over a period of 10 minutes,triethylamine (71.1 g) over a period of 30 minutes and a solution ofpotassium thiocyanate (31.0 g) in methanol (150 ml) over a period of 30minutes. The resulting mixture was stirred at -10° to -5° C. for 15minutes and at 0° to 5° C. for an additional 1.5 hours. Precipitateswere collected by filtration, washed with methanol and thereto was addedcold water (200 ml). The mixture was stirred and the precipitates werecollected by filtration, washed with cold water and dried to give methyl5-amino-1,2,4-thiadiazole-3-carboxylate (32.5 g).

(4) To a solution of ethyl cyanoformate (25.0 g) in methylene chloride(55 ml) was added 43.5% ethanolic solution of hydrogen chloride (16.8 g)with stirring at 3° C. The mixture was stirred for 5 hours at 3° to 5°C. and allowed to stand over night at -5° to -3° C. To the resultingmixture were added methylene chloride (120 ml) at below 6° C. and asolution of triethylamine (20.2 g) in methylene chloride (20 ml) over aperiod of 30 minutes at below 6° C. The mixture was stirred for 40minutes and thereto was added water (40 ml) at below 6° C. The resultingmixture was stirred for 3 minutes and the methylene chloride layer wasseparated, dried over magnesium sulfate and then evaporated. After theaddition of diisopropyl ether (40 ml) to the residue, insoluble materialwas separated by filtration and washed with diisopropyl ether (10 ml).The filtrate and washing were combined and then evaporated to give apale yellow oil of ethyl 2-imino-2-ethoxyacetate (26.2 g). A mixture ofthe oil (26.2 g) obtained above, ammonium chloride (6.42 g) in methanol(90 ml) was stirred for 2 hours at room temperature and thereto wasadded diisopropyl ether (450 ml). The mixture was ice-cooled and thenstirred for 30 minutes. Precipitates were collected by filtration togive a white powder of 1-methoxycarbonylformamidine hydrochloride (13.8g), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3350-3050, 1780, 1710, 1695, 1290, 1270, 1070, 980, 800cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.97 (3H, s), 9.8 (4H, broad s)

(5) To a solution of 1-methoxycarbonylformamidine hydrochloride (7.6 g)in methanol (55 ml) was dropwise added bromine (8.8 g) over a period of5 minutes at -5° to 0° C. To the mixture were added triethylamine (11.1g) over a period of 10 minutes and a solution of potassium thiocyanate(5.3 g) in methanol (30 ml) over a period of 20 minutes at -5° to 0° C.The mixture was stirred for 1.5 hours at 0° to 5° C. Precipitates werecollected by filtration, washed with methanol (11 ml), dried and theretowas added water (15.5 ml). The mixture was stirred for 30 minutes andprecipitates were collected by filtration, washed with water (5 ml×3)and dried to give a white powder of methyl5-amino-1,2,4-thiadiazole-3-carboxylate (6.3 g).

(6) A mixture of ethyl 2-imino-2-ethoxyacetate (36.2 g), ammoniumbromide (21.2 g) in methanol (180 ml) was stirred for 4 hours at roomtemperature and thereto was added diisopropyl ether (400 ml) withstirring. The mixture was allowed to stand for 30 minutes. Precipitateswere removed by filtration.

To the filtrate was added diisopropyl ether (200 ml) and the mixture wasallowed to stand for 10 minutes. Precipitates were collected byfiltration to give a white powder of 1-methoxycarbonylformamidinehydrobromide (16.1 g). The filtrate was concentrated to the volume ofabout 150 ml. To the concentrate was added diisopropyl ether (200 ml)and the mixture was allowed to stand for 30 minutes. Precipitates werecollected by filtration to give a white powder of the same (11.6 g).Total yield: 27.7 g.

I.R. (Nujol): 3350-3150, 1780, 1710, 1690, 1290, 1270, 1060, 980, 850,800, 730 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.91 (3H, s), 11.0 (4H, broad s)

(7) A mixture of ethyl 2-imino-2-ethoxyacetate (18.1 g), ammoniumchloride (5.8 g) in ethanol (90 ml) was stirred for 6 hours at roomtemperature. Insoluble materials were separated by filtration and washedwith ethanol. The filtrate and washing were combined and evaporated. Tothe residual oil was added acetone (50 ml). The precipitates werecollected by filtration and washed with acetone (10 ml×2) to give awhite powder of 1-ethoxycarbonylformamidine hydrochloride (1.2 g). Thefiltrate and washing were combined and evaporated. The residue waspulverized with acetone (30 ml), collected by filtration, washedsuccessively with acetone, methylene chloride and diisopropyl ether togive a white powder of the same (7.3 g). Total yield: 8.5 g.

I.R. (Nujol): 3400-3100, 1770, 1730-1680, 1650, 1300-1260, 1120, 1010,860, 760 cm⁻¹

PREPARATION 9

Preparation of Methyl 5-amino-1,2,4-thiadiazole-3-carboxylate.

To a solution of 1-ethoxycarbonylformamidine hydrobromide (16.6 g.) inabsolute methanol (84 ml) was added a solution of sodium (1.93 g) inabsolute methanol (42 ml) at 0° C. To the mixture were added alternatelybromine (12.8 g) and a solution of sodium (1.93 g) in absolute methanol(42 ml) at 0° C. and then to the suspension was added potassiumthiocyanate (8.1 g) in absolute methanol (100 ml). The reaction mixturewas stirred for an hour at 0° C. and for an additional 6 hours atambient temperature. The mixture was filtered through cellulose powderand the filtrate was evaporated to dryness. The residue was dissolved ina mixture of ethyl acetate and water, and then the ethyl acetate layerwas separated and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was triturated with diethyl ether to givethe title compound (9.0 g), mp. 202° to 205° C.

I.R. (Nujol): 3400, 3250, 3100, 1710, 1610, 1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 3.85 (3H, s), 8.25 (2H, s)

PREPARATION 10

Preparation of Methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate.

To a mixture of formic acid (33 g) and acetic anhydride (22 g) was addedmethyl 5-amino-1,2,4-thiadiazole-3-carboxylate (6.2 g), and then themixture was stirred for 2 days at ambient temperature. The reactionmixture was concentrated under reduced pressure and the residue wastriturated with a mixture of diethyl ether and n-hexane to give thetitle compound (7.2 g), mp. 210° to 215° C.

I.R. (Nujol): 3100, 1720, 1680 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 3.90 (3H, s), 8.85 (1H, s)

PREPARATION 11

Preparation of5-Formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole.

To a mixture of methyl 5-formamido-1,2,4-thiadiazole-3-carboxylate (9.2g) and methyl methylthiomethyl sulfoxide (6.1 g) inN,N-dimethylformamide (100 ml) was added 50% sodium hydride (7.1 g) withcooling in an ice-bath. The mixture was stirred for an hour at ambienttemperature and for an additional one hour at 40° C. After cooling toambient temperature, methylene chloride (300 ml) was added to thereaction mixture, and the resulting precipitates were collected byfiltration and washed with methylene chloride. The precipitates wereadded to a stirred mixture of hydrochloric acid (14.7 ml), ice-water(200 ml) and methylene chloride (200 ml). An insoluble material wasfiltered off and the methylene chloride layer was separated from thefiltrate. The solution was dried over anhydrous magnesium sulfate,evaporated and the residue was triturated with diethyl ether to give thetitle compound (4.5 g), mp. 130° to 132° C.

I.R. (Nujol): 3100, 1680, 1670 cm⁻¹

N.M.R. (d₆ -DMSO)

    ______________________________________                                        δ:    2.22                                                                                             (3H, 2s)                                                   2.28                                                                          2.68                                                                                             (2H, 2s)                                                   2.85                                                                          5.70                                                                                             (1H, 2s)                                                   5.80                                                                          8.86               (1H, s)                                        ______________________________________                                    

PREPARATION 12

Preparation ofS-methyl(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate.

A mixture of5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole(0.85 g) and sodium periodate (0.2 g) in glacial acetic acid (10 ml) wasstirred for 45 minutes at 70° C. The reaction mixture was evaporated andthe residue was dissolved in a mixture of ethyl acetate and water. Themixture was adjusted to pH 7 with an aqueous solution of sodiumbicarbonate and treated with an aqueous solution of sodium thiosulfate.The organic layer was separated, dried over anhydrous magnesium sulfateand evaporated to dryness. The residue was triturated with a mixture ofdiethyl ether and petroleum ether to give the title compound (280 mg),mp. 186° to 187° C.

I.R. (Nujol): 3100, 1680, 1660 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 2.55 (3H, s), 8.95 (1H, s)

PREPARATION 13

A mixture of5-formamido-3-(2-methylthio-2-methylsulfinylacetyl)-1,2,4-thiadiazole(10 g) and sodium periodate (2.0 g) in glacial acetic acid (50 ml) wasstirred for 50 minutes at 70° C. The solvent was evaporated and theresidue was washed with n-hexane. To the residue was added 1 N aqueoussolution of sodium hydroxide (160 ml) and the mixture was stirred for anhour at ambient temperature. To the reaction mixture was addedO-allylhydroxylamine hydrochloride (4.31 g) and the solution wasadjusted to pH 3 to 4 with 10% hydrochloric acid and then stirred for anhour at ambient temperature. After an insoluble material was filteredoff, the filtrate was washed with ethyl acetate, adjusted to pH 1 with10% hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated to dryness. The residue wastriturated with a mixture of diethyl ether and diisopropyl ether to give2-allyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer)(5.6 g), mp 169° to 172° C. (dec.).

I.R. (Nujol): 3130, 2500, 1720, 1690, 1590, 1550 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 4.79 (2H, d, J=6 Hz), 5.1-5.6 (2H, m), 5.8-6.4(1H,m), 8.88(1H,s)

PREPARATION 14

The following compounds were obtained according to a similar manner tothat of Preparation 13.

(1) 2-Benzyloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp. 90° to 95° C. (dec.).

I.R. (Nujol): 1720, 1680, 1590, 1550, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 5.28 (2H, s), 7.37 (5H, s), 8.83 (1H, s)

(2) 2-(2-Propynyloxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3570, 3360, 3260, 3120, 1720, 1670, 1550, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 3.55 (1H, t, J=2 Hz), 4.88 (2H, d, J=2 Hz), 8.85(1H, s)

(3) 2-(2-Phenoxyethoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 147° to 150° C. (dec.).

I.R. (Nujol): 3200, 1740, 1720, 1640, 1590, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.83 (1H, s)

(4) 2-Hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 240° to 241° C. (dec.).

I.R. (Nujol): 3550, 3460, 1665, 1635, 1560 cm⁻¹

PREPARATION 15

A solution of S-methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate(6.64 g) in 1 N aqueous solution of sodium hydroxide (80 ml) wasadjusted to pH 8.5 with 10% hydrochloric acid and stirred for 30 minutesat ambient temperature. On the other hand, a mixture ofN-(2,2,2-trifluoroethoxy)phthalimide (8.78 g) and hydrazine hydrate (1.7g) in ethanol (40 ml) was refluxed for 5 minutes and then cooled in anice bath. A resulting precipitates were filtered off and washed withethanol. The filtrate and the washings were combined and the combinedsolution containing 0-(2,2,2-trifluoroethyl)hydroxylamine was added tothe above aqueous solution. The mixture was adjusted to pH 3 to 4 with10% hydrochloric acid and stirred for 1.5 hours at ambient temperature.The solution was neutralized with an aqueous solution of sodiumbicarbonate, concentrated to half volume in vacuo and washed with ethylacetate. The aqueous solution was acidified with 10% hydrochloric acidand extracted with ethyl acetate. The extract was dried over magnesiumsulfate, evaporated to dryness and the residue was triturated withdiisopropyl ether to give2-(2,2,2-trifluoroethoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer)(2.46 g), mp. 180° to 185° C. (dec.).

N.M.R. (d₆ -DMSO): δ: 4.80 and 5.07 (2H, ABq, J=9 Hz), 8.85 (1H, s)

PREPARATION 16

The following compounds were obtained according to a similar manner tothat of Preparation 15.

(1) 2-Methylthiomethoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 146° to 148° C. (dec.).

I.R. (Nujol): 3300, 2600, 2550, 1730, 1705, 1680, 1600, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 2.23 (3H, s), 5.40 (2H, s), 8.87 (1H, s)

(2)2-(2-Methylthioethoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

I.R. (Nujol): 3230, 1720, 1690, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 2.17 (3H, s), 2.82 (2H, t, J=7 Hz), 4.42 (2H, t,J=7 Hz), 8.87 (1H, s)

(3) 2-Phenoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 145° to 147° C. (dec.).

I.R. (Nujol): 3130, 1720, 1690, 1585, 1550 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.0-7.6 (5H, m), 8.88 (1H, s)

(4)2-[2-(2-Hexyloxyethoxy)ethoxyimino]-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

I.R. (CHCl₃): 3420, 3180, 1740, 1700, 1600, 1530, 1460 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 0.87 (3H, t, J=5 Hz), 0.87-1.73 (8H, m), 3.20-3.90(8H, m), 4.23-4.53 (2H, m), 8.84 (1H, s), 13.55 (1H, broad s)

(5) 2-Trityloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(anti isomer), mp. 188° to 190° C. (dec.).

I.R. (Nujol): 3150, 1620, 1600, 1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.00 (15H, s), 8.92 (1H, s)

PREPARATION 17

A mixture of S-methyl(5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate(6 g) and an aqueous solution (50 ml) of sodium hydroxide (4.2 g) wasstirred for an hour at 50° to 55° C. The mixture was cooled to ambienttemperature and adjusted to pH 7 with 10% hydrochloric acid. On theother hand, a mixture of N-(ethoxycarbonylmethoxy)phthalimide (12.9 g)and hydrazine hydrate (2.08 g) in ethanol (60 ml) was refluxed for 5minutes and cooled in an ice bath. A resulting precipitate was filteredoff and washed with ethanol. The filtrate and the washings were combinedand the combined solution containingO-(ethoxycarbonylmethyl)hydroxylamine was added to the above aqueoussolution. The mixture was adjusted to pH 3 to 4 with 10% hydrochloricacid and stirred for 1.5 hours at ambient temperature. The solution wasneutralized with an aqueous solution of sodium bicarbonate, concentratedto half volume in vacuo and washed with ethyl acetate. The aqueoussolution was acidified with 10% hydrochloric acid and extracted withethyl acetate. The extract was dried over magnesium sulfate, evaporatedto dryness and the residue was triturated with diisopropyl ether to give2-ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.8 g), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3500,3330,3210,2670,2550,1740,1610,1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 1.24 (3H,t, J=7 Hz), 4.14 (2H,q, J=7 Hz), 4.80(2H, s), 8.15 (2H, broad s)

PREPARATION 18

The following compounds were obtained according to a similar manner tothat of Preparation 17.

(1) 2-Cyanomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp. 130° to 135° C. (dec.).

I.R. (Nujol): 3350,3150,1730,1630, 1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 5.17 (2H, s), 8.28 (2H, broad s)

(2)2-(1-Ethoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 165° to 168° C. (dec.).

I.R. (Nujol): 3450,3350,3240,1750,1730,1630,1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 1.18 (3H,t,J=7 Hz), 1.50 (6H,s), 4.15 (2H, q, J=7Hz), 8.23 (2H, broad s)

(3) 2-(N,N-Diethylcarbamoylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer), mp. 150° to 155° C.(dec.).

I.R. (Nujol): 3400,3150,1745,1635,1610,1595,1535 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 1.03 (3H,t,J=7 Hz), 1.10 (3H, t, J=7 Hz), 3.28(4H, q, J=7 Hz), 4.90 (2H,s), 8.23 (2H, broad s)

(4) 2-Mesylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer).

I.R. (Nujol): 3450, 3400, 3270, 2600, 2460, 1735, 1640, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 3.00(3H, s), 5.38 (2H,s), 8.22 (2H, broad s)

PREPARATION 19

The following compounds were obtained according to a similar manner tothat of Preparation 4.

(1) 2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 93° to 95° C. (dec.).

I.R. (Nujol): 3430, 3100, 1710, 1615,1525 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 4.72 (2H, d, J=6 Hz), 5.1-5.5 (2H, m), 5.7-6.3(1H, m), 8.17 (1H, broad s)

(2) 2-Benzyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 158° to 160° C. (dec.).

I.R. (Nujol): 3430, 3380, 3260, 1730, 1640, 1610, 1535 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 5.22 (2H, s), 7.33 (5H, s), 8.17 (2H, broad s)

(3) 2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp. 155° to 157° C. (dec.).

I.R. (Nujol): 3500, 3310, 3160, 2600, 2480, 1745, 1610, 1535 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 3.53 (1H, t, J=2 Hz), 4.87 (2H, d, J=2 Hz), 8.23(2H, broad s)

(4) 2-(2-Phenoxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 150° to 153° C. (dec.).

I.R. (Nujol): 3470, 3300, 3150, 2550, 1750, 1620, 1600, 1540, 1500 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 4.0-4.7 (4H, m), 6.7-7.5 (5H, m), 8.20 (2H, broads)

(5)2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 140° to 143° C. (dec.).

I.R. (Nujol): 3450, 3350, 3260, 1745, 1670, 1645, 1615, 1515 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 4.72 and 4.95 (2H, ABq, J=9 Hz), 8.25 (2H, broads)

(6) 2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 140° to 143° C. (dec.).

I.R. (Nujol): 3500, 3300, 3150, 2670, 2580, 1740, 1615, 1605, 1530 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 2.22 (3H, s), 5.33 (2H, s), 8.20 (2H, broad s)

(7) 2-(2-Methylthioethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 140° to 143° C. (dec.).

I.R. (Nujol): 3430, 3340, 3230, 2650, 2450, 1720, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 2.08 (3H, s), 2.72 (2H, t, J=7 Hz), 4.28 (2H, t,J=7 Hz), 8.17 (2H, broad s)

(8) 2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 145° to 147° C. (dec.).

I.R. (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.0-7.5 (5H, m), 8.30 (2H, broad s)

(9)2-[2-(2-Hexyloxyethoxy)ethoxyimino]-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

I.R. (CHCl₃): 3350, 3230, 2600, 2500, 1730, 1620, 1520, 1460 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 0.87 (3H, t, J=5 Hz), 0.87-1.73 (8H, m), 3.20-3.90(8H, m), 4.13-4.47 (2H, m), 8.17 (2H, broad s)

(10) 2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp. 173° to 174° C. (dec.).

I.R. (Nujol): 3450, 1735, 1620, 1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.35 (15H, s), 8.22 (2H, s)

(11) 2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (antiisomer), mp. 170° to 171° C.

I.R. (Nujol): 3300, 3150, 1680, 1635, 1520 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.33 (15H, s), 8.13 (2H, s)

PREPARATION 20

A mixture of 2-hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (3.3 g) and dichloroacetyl chloride (9.0 g) inmethylene chloride (50 ml) was stirred for 6.5 hours at ambienttemperature. A resulting precipitates were filtered and dissolved inethyl acetate. After removing of an insoluble substance by filtration,the filtrate was evaporated to dryness. The residue was triturated withdiisopropyl ether to give2-dichloroacetoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (2.3 g) mp. 123° C.

I.R. (Nujol): 3150, 1790, 1690, 1550 cm⁻¹

PREPARATION 21

To a mixture of2-hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (9.5 g) and dimethylformamide (80 ml) was added with stirring atambient temperature trityl chloride (22.8 g), and triethylamine (4.1 g)was gradually added thereto after 3 minutes stirring. The resultingmixture was stirred for 10 minutes and ethyl acetate (250 ml) was addedthereto. The mixture was washed three times with water and with asaturated aqueous solution of sodium chloride, dried over magnesiumsulfate and concentrated. To the residue were added an aqueous solutionof sodium bicarbonate (50 ml) and diisopropyl ether (100 ml).Precipitates were collected by filtration and the aqueous layer in thefiltrate was separated. The collected precipitates were suspended in theseparated aqueous layer and ethyl acetate was added thereto. The mixturewas adjusted to pH 2 with 10% hydrochloric acid and extracted with ethylacetate. The extract was dried over magnesium sulfate and concentratedin vacuo. The residue was washed with hexane to give2-trityloxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (17.1 g), mp. 175° to 176° C. (dec.).

I.R. (Nujol): 3180, 3070, 1700, 1600, 1540 cm⁻¹

N.M.R. (d₆ -DMSO): δ: 7.35 (15H, s), 8.83 (1H, s), 13.52 (1H, broad s)

PREPARATION 22

(1) A solution of N-(3-aminopropyl)acetamide (146 g) in dioxane (710 ml)was added to a solution of 97% sodium hydroxide (52 g) in water (620 ml)and then carbon disulfide (96 g) was added dropwise thereto over 35minutes at -1° to 3° C. The mixture was stirred for 1 hour at 0° to 2°C. To the mixture containing sodium N-(3-acetamidopropyl)dithiocarbamatewas added dropwise methyl iodide (179 g) over 35 minutes at 0° to 5° C.and then the resulting mixture was stirred for 3 hours at the sametemperature. Dioxane was distilled off in vacuo from the reactionmixture and the residue was extracted with ethyl acetate (300 ml, 200ml×4). The extracts were dried over magnesium sulfate and concentratedin vacuo to give oil of methyl N-(3-acetamidopropyl)dithiocarbamate(193.18 g).

(2) A mixture of a solution of methylN-(3-acetamidopropyl)dithiocarbamate (193 g) in dioxane (610 ml) and asolution of sodium azide (79.42 g) in water (500 ml) was refluxed understirring for 4 hours. Dioxane was distilled off and the remainingaqueous layer was washed with diethyl ether (150 ml×2), adjusted to pH 1with 17.5% hydrochloric acid, and cooled in an ice bath. Precipitateswere collected by filtration and washed with ice-water to give whitepowder of 1-(3-acetamidopropyl)-1H-tetrazol-5-thiol (91.75 g), mp. 152°to 154° C.

N.M.R. (d₆ -DMSO): δ: 1.87 (3H, s), 1.97 (2H, m), 3.17 (2H, m), 4.28(2H, t, J=7 Hz), 7.9 (1H, broad s), 15.0 (1H, broad s)

(3) A mixture of 1-(3-acetamidopropyl)-1H-tetrazole-5-thiol (85 g) and 6N hydrochloric acid (1 l) was refluxed for 75 minutes under stirring.The reaction mixture was concentrated in vacuo and precipitates werecollected by filtration and washed with hexane and diethyl ether to give1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (67.15 g).

N.M.R. (D₂ O): δ: 2.45 (2H, m), 3.23 (2H, t, J=7 Hz), 4.50 (2H, t, J=7Hz)

(4) A solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (12.3g) in dioxane (30 ml) was added under ice-cooling to a stirred solutionof 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (9.78 g) andtriethylamine (11.1 g) in a mixture of dioxane (25 ml) and water (25ml), and then the resulting mixture was stirred for 1.75 hours atambient temperature. Dioxane was distilled off and to the residue wereadded diethyl ether and a small amount of water. After shaking, theaqueous layer was separated and the organic layer was extracted twicewith 10% potassium carbonate. The extracts combined with the separatedaqueous layer were washed three times with diethyl ether, adjusted to pH1 with hydrochloric acid and extracted with diethyl ether. The extractwas washed with water, dried and evaporated in vacuo. The residual oil(10.92 g) was pulverized with diisopropyl ether to give1-[3-(N-t-butoxycarbonylamino)propyl]-1H-tetrazole-5-thiol (9.6 g), mp.75° to 77° C.

I.R. (Nujol): 3380, 3260, 1650, 1530, 1170, 1050 cm⁻¹

N.M.R. (CDCl₃): δ: 1.50 (9H, s), 2.14 (2H, m), 3.25 (2H, m), 4.39 (2H,t, J=7 Hz), 4.9-6.7 (1H, broad)

EXAMPLE 1

To a cold solution of phosphorus pentachloride (450 mg) in methylenechloride (10 ml) was added2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (650 mg) at -15° C. and the mixture was stirred for 30minutes at the same temperature. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(785 mg) and trimethylsilylacetamide (2.1 g) in methylene chloride (10ml) was warmed to make a clear solution and then cooled to -20° C. Thesolution was added to the above activated mixture at -20° C. and themixture was stirred for 40 minutes at -15° C. The reaction mixture waspoured into cold aqueous solution of sodium bicarbonate (20 ml) andstirred at ambient temperature for 30 minutes. Methylene chloride wasdistilled off and ethyl acetate was added to the residual aqueoussolution. The mixture was adjusted to pH 3 or 4 with 10% hydrochloricacid and extracted with ethyl acetate. The extract was dried overmagnesium sulfate, treated with an activated charcoal and evaporated todryness. The residue was triturated with diethyl ether andreprecipitated from a mixed solvent of acetone and diethyl ether.Precipitates were dissolved in an aqueous solution of sodium bicarbonateand the solution was adjusted to pH 1 or 2 with 10% hydrochloric acid togive precipitates. The precipitates were collected by filtration andwashed with water to give7-[2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.35 g), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 4.27 and 4.50 (2H, ABq, J=14Hz), 5.17 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 7.00-7.50 (4H,m), 8.22 (2H, s), 9.50 (1H, s), 9.80 (1H, d, J=8 Hz).

EXAMPLE 2

To a cold solution of phosphorus pentachloride (1.04 g) in methylenechloride (25 ml) was added2-(4-fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.4 g) at -15° C. and the mixture was stirred for 30minutes at the same temperature. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.65 g) and trimethylsilylacetamide (5 g) in methylene chloride (25 ml)was warmed to make a clear solution and then cooled to -15° C. Thesolution was added to the above activated mixture and the mixture wasstirred for 1 hour at 0° to 5° C. The reaction mixture was concentratedand to the residue were added ethyl acetate and water. After filteringoff an insoluble material, the ethyl acetate layer was poured into anaqueous solution of sodium bicarbonate. The aqueous layer was separatedout, adjusted to pH 4 with 10% hydrochloric acid after addition of ethylacetate and extracted with ethyl acetate. The extract was dried overmagnesium sulfate and evaporated to a volume of about 10 ml.Precipitates were collected by filtration, washed with ethyl acetate anddiethyl ether and dried to give7-[2-(4-fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.2 g), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.57 and 3.80 (2H, ABq, J=18 Hz), 4.27 and 4.57(2H, ABq, J=13 Hz), 5.20 (1H, d, J=4 Hz), 5.87 (1H, dd, J=4 and 8 Hz),7.17-7.3 (4H, m), 8.20 (2H, s), 9.50 (1H, s), 9.83 (1H, d, J=8 Hz)

EXAMPLE 3

To a cold solution of phosphorus pentachloride (2.08 g) in methylenechloride (50 ml) was added at -15° C.2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)(2.64 g) and the mixture was stirred for 30 minutes at the sametemperature. On the other hand, a mixture of 4-nitrobenzyl7-amino-3-cephem-4-carboxylate (3.35 g) and trimethylsilylacetamide (10g) in methylene chloride (50 ml) was warmed to make a clear solution andthen cooled to -15° C. The solution was added to the above activatedmixture and the mixture was stirred for 0.5 hour at 0° to 5° C. Thereaction mixture was poured into cold aqueous solution (100 ml) ofsodium bicarbonate (5.9 g). The methylene chloride layer was dried overmagnesium sulfate and evaporated to dryness. The residue was pulverizedwith diethyl ether. The resulting powder was collected by filtration anddried to give 4-nitrobenzyl 7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer) (5.1 g), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.60 (2H, broad s), 5.23 (1H, d, J=4 Hz), 5.42(2H, s), 6.00 (1H, dd, J=4 and 8 Hz), 6.67 (1H, t, J=4 Hz), 7.0-7.50(5H, m), 7.73 (2H, d, J=8 Hz), 8.27 (2H, d, J=8 Hz), 8.30 (2H, s), 9.97(1H, d, J=8 Hz)

EXAMPLE 4

The following compounds were obtained according to similar manners tothose of Examples 1 to 3, 5 and 7 to 12.

(1)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3400, 3200, 1770, 1700, 1660, 1620, 1580, 1510 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.23 and 4.50 (2H, ABq, J=14Hz), 5.17 (1H, d, J=4 Hz), 5.30 (2H, s), 5.89 (1H, dd, J=4 and 8 Hz),7.0-7.5 (5H, m), 8.22 (1H, s), 9.83 (1H, d, J=8 Hz)

(2)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.)

I.R. (Nujol): 3450, 3350, 3180, 1780, 1710, 1680, 1610, 1590, 1510 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.28 and 4.45 (2H, ABq, J=13Hz), 4.83-5.10 (2H, m), 5.18 (1H, d, J=4 Hz), 5.20-5.43 (2H, m), 5.93(1H, dd, J=4 and 8 Hz), 5.67-6.30 (1H, m), 7.0-7.57 (5H, m), 8.30 (2H,s), 9.92 (1H, d, J=8 Hz)

(3)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 158° C. (dec.)

I.R. (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1620, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.77 (2H, broad s), 3.95 (3H, s), 4.33 (2H, broads), 5.27 (1H, d, J=4 Hz), 5.93 (1H, dd, J=4 and 8 Hz), 7.0-7.67 (5H, m),8.37 (2H, s), 10.0 (1H, d, J=8 Hz)

(4)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 150° to 155° C. (dec.)

I.R. (Nujol): 3450, 3350, 3180, 1775, 1710, 1680, 1610, 1580, 1515 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.03 (3H, s), 3.62 (2H, broad s), 4.77 and 5.03(2H, ABq, J=14 Hz), 5.28 (1H, d, J=4 Hz), 5.97 (1H, dd, J=4 and 8 Hz),7.0-7.67 (5H, m), 8.37 (2H, s), 9.97 (1H, d, J=8 Hz)

(5)7-[2-(2-Methoxy-5-nitrophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 169° C. (dec.)

I.R. (Nujol): 3380, 3220, 3100, 1780, 1690, 1620, 1600, 1520, 1340,1280, 1085, 1065, 820, 750 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.71 (2H, m), 3.98 (3H, s), 4.25 and 4.66 (2H,ABq, J=14 Hz), 5.23 (1H, d, J=5 Hz), 5.94 (1H, dd, J=5 and 9 Hz), 7.33(1H, d, J=8 Hz), 8.10 (1H, d, J=8 Hz), 8.19 (1H, s), 8.34 (2H, broad s),9.58 (1H, s), 9.87 (1H, d, J=9 Hz)

(6)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazol[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1670, 1615, 1520, 1495 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.80 (2H, broad s), 4.30 and 4.65 (2H, ABq, J=13Hz), 5.27 (1H, d, J=5 Hz), 5.95 (1H, dd, J=5 and 8 Hz), 7.25 (2H, s),7.35 (2H, s), 7.80 (1H, d, J=10 Hz), 8.37 (2H, broad s), 8.62 (1H, d,J=10 Hz), 9.92 (1H, d, J=8 Hz)

(7) 4-Nitrobenzyl7-[2-(4-fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1625, 1605, 1500, 1495 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.45-3.75 (2H, m), 5.15 (1H, d, J=5 Hz), 5.35 (2H,s), 5.92 (1H, dd, J=5 and 8 Hz), 6.58 (1H, t, J=4 Hz), 7.08 (2H, s),7.18 (2H, s), 7.60 (2H, d, J=8 Hz), 8.13 (2H, d, J=8 Hz), 8.17 (2H,broad s), 9.75 (1H, d, J=8 Hz)

(8)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3450, 3280, 3180, 1760, 1720, 1660, 1620, 1580, 1520, 1480cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.72 (2H, broad s), 4.27 and 4.55 (2H, ABq, J=13Hz), 4.80 (2Hz, s), 5.22 (1H, d, J=5 Hz), 5.88 (1H, dd, J=5 and 8 Hz),7.25 (2H, d, J=9 Hz), 7.42 (2H, d, J=9 Hz), 8.23 (2H, broad s), 9.85(1H, d, J=8 Hz)

(9)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3250, 3170, 1765, 1700, 1680, 1650, 1615, 1580,1510, 1480 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.27 and 4.48 (2H, ABq, J=13Hz), 5.22 (1H, d, J=5 Hz), 5.30 (2H, s), 5.93 (1H, dd, J=5 and 8 Hz),7.35 (2H, d, J=9 Hz), 7.48 (2H, d, J=9 Hz), 8.37 (2H, broad s), 9.97(1H, d, J=8 Hz)

(10)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3400, 3270, 3180, 1770, 1620, 1580, 1520, 1480 cm^(<1)

N.M.R. (d₆ -DMSO, δ): 1.45 (3H, d, J=7 Hz), 3.60-4.10 (1H, m), 5.20 (1H,d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 6.62 (1H, d, J=6 Hz), 7.35 (2H,d, J=9 Hz), 7.48 (2H, d, J=9 Hz), 8.03-8.73 (2H, m), 9.97 (1H, d, J=8Hz)

(11) 4-Nitrobenzyl7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.62 (2H, broad s), 5.18 (1H, d, J=5 Hz), 5.38(2H, s), 5.95 (1H, dd, J=5 and 8 Hz), 6.63 (1H, t, J=4 Hz), 7.25 (2H, d,J=9 Hz), 7.38 (2H, d, J=9 Hz), 7.65 (2H, d, J=8 Hz), 8.20 (2H, d, J=8Hz), 8.23 (2H, broad s), 9.85 (1H, d, J=8 Hz)

(12)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 125° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1670, 1615, 1580, 1520, 1480 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.50-3.93 (4H, m), 4.12-4.48 (4H, m), 5.18 (1H, d,J=5 Hz), 5.88 (1H, dd, J=5 and 8 Hz), 7.28 (2H, d, J=9 Hz), 7.45 (2H, d,J=9 Hz), 8.30 (2H, broad s), 9.94 (1H, d, J=8 Hz)

(13)7-[2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), decomposed by 200° C.

I.R. (Nujol): 3600, 3400, 1770, 1720, 1680, 1530, 1250, 1120, 970 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.03 (3H, s), 3.60 (2H, m), 4.65 and 5.05 (2H,ABq, J=15 Hz), 5.27 (1H, d, J=5 Hz), 5.97 (1H, dd, J=5 and 8 Hz),7.13-7.77 (3H, m), 8.35 (2H, m), 9.90 (1H, d, J=8 Hz)

(14)7-[2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 160° C.

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1205, 1060 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.77 (2H, m), 4.28 and 4.68 (2H, ABq, J=14 Hz),5.37 (1H, d, J=5 Hz), 5.97 (1H, dd, J=5 and 8 Hz), 7.16-7.80 (3H, m),8.36 (2H, s), 9.60 (1H, s), 9.93 (1H, d, J=8 Hz)

(15) 4-Nitrobenzyl7-[2-(3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 136° to 140° C. (dec.).

I.R. (Nujol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520,1450, 1325, 1280, 1160, 1125, 975, 850, 740 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.7 (2H, m), 5.22 (1H, d, J=5 Hz), 5.37 (2H, s),5.99 (1H, dd, J=5 and 8 Hz), 6.63 (1H, m), 7.50 (4H, broad s), 7.66 (2H,d, J=9 Hz), 8.20 (2H, d, J=9 Hz), 9.89 (1H, d, J=8 Hz)

(16)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 164° C.

I.R. (Nujol): 3300, 3180, 1765, 1670, 1610, 1520, 1320, 1165, 1120,1060, 930, 790, 700 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.73 (2H, m), 4.23 and 5.63 (2H, ABq, J=14 Hz),5.27 (1H, d, J=5 Hz), 5.93 (1H, dd, J=5 and 8 Hz), 7.55 (4H, broad s),8.34 (2H, broad s), 9.60 (1H, s), 9.99 (1H, d, J=8 Hz)

(17)7-[2-(3-Ethoxycarbonylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 162° C.

I.R. (Nujol): 3350-3150, 1770, 1720-1660, 1620, 1520, 1290, 1270, 1100,1060, 900, 760 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.32 (3H, t, J=7 Hz), 3.71 (2H, m), 4.25 and 4.60(2H, ABq, J=14 Hz), 4.32 (2H, q, J=7 Hz), 5.23 (1H, d, J=5 Hz), 5.73(1H, dd, J=5 and 8 Hz), 7.40-7.95 (4H, m), 8.67 (2H, broad s), 9.59 (1H,s), 9.98 (1H, d, J=8 Hz)

(18)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.50-3.83 (4H, m), 4.0-4.53 (4H, m), 5.13 (1H, d,J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 7.12 (2H, s), 7.23 (2H, s), 8.18(2H, s), 9.77 (1H, d, J=8 Hz)

(19)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.57 (2H, broad s), 4.27 and 4.53 (2H, ABq, J=14Hz), 5.23 (1H, d, J=8 Hz), 5.37 (2H, s), 5.93 (1H, dd, J=4 and 8 Hz),7.25 (2H, s), 7.37 (2H, s), 8.32 (2H, s), 9.92 (1H, d, J=8 Hz)

(20)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1710, 1620, 1540, 1520, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.67 and 3.90 (2H, ABq, J=18 Hz), 4.13 and 4.37(2H, ABq, J=13 Hz), 4.73 (2H, s), 5.23 (1H, d, J=4 Hz), 5.90 (1H, dd,J=4 and 8 Hz), 7.08 (1H, d, J=10 Hz), 7.17 (2H, s), 7.28 (2H, s), 7.72(1H, d, J=10 Hz), 8.23 (2H, s), 9.83 (1H, d, J=8 Hz)

(21)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1700, 1620, 1520, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.90 (2H, t, J=6 Hz), 3.70 (2H, broad s), 4.40(2H, t, J=6 Hz), 4.27 and 4.47 (2H, ABq, J=13 Hz), 5.17 (1H, d, J=4 Hz),5.87 (1H, dd, J=4 and 8 Hz), 7.15 (2H, s), 7.25 (2H, s), 8.22 (2H, s),9.83 (1H, d, J=8 Hz)

(22)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3450, 3350, 3150, 1780, 1705, 1670, 1610, 1510 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.66 and 3.84 (2H, ABq, J=18 Hz), 4.30 and 4.50(2H, ABq, J=14 Hz), 5.00 (2H, d, J=5 Hz), 5.24 (1H, d, J=4 Hz),5.20-5.40 (2H, m), 5.96 (1H, dd, J=4 and 8 Hz), 5.80-6.20 (1H, m), 7.28(2H, s), 7.34 (2H, s), 8.32 (2H, s), 9.96 (1H, d, J=8 Hz)

(23)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 156° to 161° C. (dec.).

I.R. (Nujol): 3450, 3300, 3200, 1770, 1730, 1680, 1610, 1510, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.04 (3H, s), 3.52 and 3.68 (2H, ABq, J=18 Hz),4.74 and 5.02 (2H, ABq, J=14 Hz), 5.26 (1H, d, J=4 Hz), 5.94 (1H, dd,J=4 and 8 Hz ), 7.26 (2H, s), 7.34 (2H, s), 8.30 (2H, s), 9.94 (1H, d,J=8 Hz)

(24)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1615, 1585, 1520 cm⁻¹

(25)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1590, 1520 cm⁻¹

(26)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 193° C.

I.R. (Nujol): 3450, 3320, 3200, 1770, 1710, 1665, 1630, 1560, 1515,1325, 1170, 1110, 940 cm⁻¹

(27)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 168° to 170° C. (dec.).

I.R. (Nujol): 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540 cm⁻¹

(28)7-[2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3260, 3180, 1775, 1675, 1625, 1600, 1520, 1480 cm⁻¹

(29)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

I.R. (Nujol): 3400, 3270, 3180, 1765, 1675, 1605, 1500 cm⁻¹

(30)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3250, 1760, 1670, 1620, 1590, 1520 cm⁻¹

EXAMPLE 5

To a cold solution of phosphorus pentachloride (2.08 g) in methylenechloride (45 ml) was added2-(t-butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.51 g) at -17° C. and the mixture was stirred for 50minutes at the same temperature. On the other hand, a mixture of7-amino-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (3.34 g) and trimethylsilylacetamide (12 g) in methylene chloride(45 ml) was warmed to make a clear solution and then cooled to -20° C.The solution was added to the above activated mixture and the mixturewas stirred for 1 hour at -10° to -15° C. The reaction mixture wasevaporated and to the residue were added ethyl acetate and an aqueoussolution of sodium bicarbonate. The aqueous layer was separated out,adjusted to pH 3 to 4 with 10% hydrochloric acid and extracted withethyl acetate. The extract was dried over magnesium sulfate andevaporated under reduced pressure. The residue was triturated withdiethyl ether to give7-[2-(t-butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.4 g), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1770, 1720, 1680, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.47 (9H, s), 3.73 (2H, broad s), 4.28 and 4.60(2H, ABq, J=13 Hz), 4.65 (2H, s), 5.18 (1H, d, J=5 Hz), 5.87 (1H, dd,J=5 and 8 Hz), 7.78 (1H, d, J=10 Hz), 8.17 (2H, broad s), 8.62 (1H, d,J=10 Hz), 9.55 (1H, d, J=8 Hz)

EXAMPLE 6

The following compounds were obtained according to similar manners tothose of Examples 1 to 3, 5 and 7 to 12.

(1)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 114° to 119° C. (dec.).

N.M.R. (d₆ -DMSO, δ): 1.40 (9H, s), 1.74 (3H, s), 1.80 (2H, m), 3.00(4H, m), 4.14 (2H, m), 5.10 (1H, d, J=5 Hz), 5.72 (1H, dd, J=5 and 8Hz), 6.70 (1H, broad s), 8.10 (2H, broad s), 9.44 (1H, d, J=8 Hz)

(2) 4-Nitrobenzyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylate(syn isomer), mp 91° to 100° C. (dec.).

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.38 (9H, s), 1.80 (2H, m), 3.06 (2H, m),3.7-4.3 (4H, m), 5.33 (1H, d, J=5 Hz), 5.49 (2H, s), 5.95 (1H, d, J=5Hz), 7.74 (2H, d, J=9 Hz), 8.92 (2H, d, J=9 Hz)

(3)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 107° to 112° C. (dec.).

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.32 (9H, s), 1.34 (9H, s), 1.80 (2H, m),3.10 (2H, m), 3.30 (2H, m), 3.70 (2H, m), 4.0-4.5 (6H, m), 5.13 (1H, d,J=5 Hz), 5.83 (1H, d, J=5 Hz).

(4) 4-Nitrobenzyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.60 (2H, broad s), 4.57-4.83 (2H, m), 5.17 (1H,d, J=4 Hz), 5.0-5.35 (2H, m), 5.40 (2H, s), 5.93 (1H, dd, J=4 and 8 Hz),5.87-6.17 (1H, m), 6.63 (1H, t, J=3 Hz), 7.70 (2H, d, J=9 Hz), 8.10 (2H,s), 8.23 (2H, d, J=9 Hz), 9.57 (1H, d, J=8 Hz)

(5)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 185° to 195° C. (dec.).

I.R. (Nujol): 3470, 3330, 3210, 3060, 1770, 1735, 1700, 1670, 1620,1555, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.00 (3H, s), 3.53 (2H, broad s), 4.65 and 4.87(2H, ABq, J=9 Hz), 4.70 and 4.93 (2H, ABq, J=13 Hz), 5.12 (1H, d, J=5Hz), 5.78 (1H, dd, J=5 and 8 Hz), 8.12 (2H, broad s), 9.62 (1H, d, J=8Hz)

(6)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.68 (2H, broad s), 4.30 and 4.40 (2H, ABq, J=13Hz), 4.68 and 4.92 (2H, ABq, J=9 Hz), 4.87-5.10 (2H, m), 5.15 (1H, d,J=5 Hz), 5.17-5.47 (2H, m), 5.83 (1H, dd, J=5 and 8 Hz), 5.67-6.27 (1H,m), 8.25 (2H, broad s), 9.77 (1H, d, J=8 Hz)

(7)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 3.95 (3H, s), 4.32 (2H, broads), 4.68 and 4.92 (2H, ABq, J=9 Hz), 5.15 (1H, d, J=5 Hz), 5.85 (1H, dd,J=5 and 8 Hz), 8.25 (2H, broad s), 9.75 (1H, d, J=8 Hz)

(8)7-[2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 215° to 220° C. (dec.).

I.R. (Nujol): 3230, 3150, 1775, 1680, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.37 (9H, s), 1.43 (3H, d, J=7 Hz), 3.0-3.5(2H, m), 4.0-4.4 (2H, m), 5.10 (1H, d, J=4.5 Hz), 5.8-6.1 (1H, m), 6.53(1H, d, J=6.9 Hz)

(9)7-[2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 181° to 186° C. (dec.).

I.R. (Nujol): 3320,1780, 1680, 1620, 1520, 1165 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.32 (18H, s), 3.07-3.52 (4H, m), 3.7 (2H,broad s), 4.0-4.5 (6H, m), 5.15 (1H, d, J=4.5 Hz), 5.85 (1H, d, J=4.5Hz), 8.23 (2H, broad s)

(10)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 147° to 161° C. (dec.).

I.R. (Nujol): 3420, 1780, 1680, 1615, 1525 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 2.72 (3H, s), 3.73 (2H, broad s), 4.30 and4.67 (2H, ABq, J=14 Hz), 5.35 (1H, d, J=5.0 Hz), 6.15 (1H, d, J=5.0 Hz),7.50 (15H, s)

(11)7-[2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° C. (dec.).

I.R. (Nujol): 3305, 3160, 1770,1670, 1520, 1245 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.37 (9H, s), 3.0-3.5 (2H, m), 3.72 (2H,broad s), 3.9-4.3 (2H, m), 4.1-4.6 (2H, m), 5.13 (1H, d, J=4.5 Hz), 5.33(2H, s), 5.7-6.0 (1H, m)

(12)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3175, 1770, 1720, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50 (9H, s), 3.73 (2H, broad s), 4.33 and 4.58(2H, ABq, J=13 Hz), 4.65 (2H, s), 5.17 (1H, d, J=4 Hz), 5.85 (1H, dd,J=4 and 8 Hz), 8.18 (2H, s), 9.50 (1H, d, J=8 Hz), 9.53 (1H, s)

(13)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50 (9H, s), 2.10 (3H, s), 3.62 (2H, broad s),4.68 (2H, s), 4.77 and 5.03 (2H, ABq, J=13 Hz), 5.20 (1H, d, J=4 Hz),5.88 (1H, dd, J=4 and 8 Hz), 8.18 (2H, s), 9.55 (1H, d, J=8 Hz)

(14)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

I.R. (Nujol): 3400, 3280, 3180, 1770, 1720, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.42 (9H, s), 3.67 (2H, broad s), 4.27 and 4.43(2H, ABq, J=13 Hz, )4.62 (2H, s), 4.87-5.07 (2H, m), 5.10 (1H, d, J=5Hz), 5.13-5.43 (2H, m), 5.82 (1H, dd, J=5 and 8 Hz), 5.60-6.20 (1H, m),8.10 (2H, broad s), 9.47 (1H, d, J=8 Hz)

(15)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 110° to 115° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.32 (9H, s), 1.42 (9H, s), 3.33 (2H, broad s),3.53-3.80 (2H, m), 4.13-4.47 (4H, m), 4.58 (2H, s), 5.08 (1H, d, J=5Hz), 5.78 (1H, dd, J=5 and 8 Hz), 8.07 (2H, broad s), 9.45 (1H, d, J=8Hz)

(16)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-phenyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1775, 1720, 1685, 1620, 1525, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.43 (9H, s), 3.70 (2H, broad s), 4.32 and 4.57(2H, ABq, J=13 Hz), 4.65 (2H, s), 5.12 (1H, d, J=5 Hz), 5.85 (1H, dd,J=5 and 8 Hz), 7.67 (5H, s), 8.17 (2H, broad s), 9.50 (1H, d, J=8 Hz)

(17)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 133° to 146° C. (dec.).

I.R. (Nujol): 3280, 3170, 1775, 1685, 1670, 1625, 1520 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.40 (9H, s), 1.46 (3H, d, J=7 Hz), 1.56-2.06(2H, m), 3.03 (2H, t, J=7 Hz), 3.1-4.1 (1H, m), 4.23 (2H, t, J=7 Hz),5.13 (1H, d, J=5 Hz), 5.97 (1H, d, J=5 Hz), 6.65 (1H, d, J=6.5 Hz)

(18)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm⁻¹

(19)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

(20)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

(21)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3180, 1760, 1670, 1610, 1520 cm⁻¹

(22)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

I.R. (Nujol): 3420, 3300, 3190, 1770, 1705, 1670, 1620, 1525 cm⁻¹

(23)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer), mp 111° to 115° C. (dec.).

I.R. (Nujol): 3300-3100, 1780, 1690-1660, 1520, 1270 cm⁻¹

(24)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

(25)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 184° to 196° C. (dec.).

I.R. (Nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm⁻¹

(26)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 198° C. (dec.).

I.R. (Nujol): 3250, 3160, 1760, 1650, 1615, 1522, 1020 cm⁻¹

(27)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm⁻¹

(28)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 cm⁻¹

(29)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1520 cm⁻¹

(30)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 195° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1575, 1520, 1400 cm⁻¹

(31)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 182° to 187° C. (dec.).

I.R. (Nujol): 3260, 3150, 1758, 1660, 1616, 1575, 1520, 1400 cm⁻¹

(32)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520 cm⁻¹

(33)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 195° C. (dec.).

I.R. (Nujol): 3300-3100, 1770-1740, 1660, 1620, 1570, 1520, 1280, 1170,1060, 1020 cm⁻¹

(34)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 205° C. (dec.).

I.R. (Nujol): 3400-3150, 1760, 1660, 1630-1590, 1520, 1340, 1170, 1030cm⁻¹

(35)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 182° to 187° C. (dec.).

I.R. (Nujol): 3350, 3150, 1760, 1660, 1625, 1565, 1520 cm⁻¹

(36)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3250, 1755, 1660, 1590, 1520 cm⁻¹

(37)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3170, 1760, 1670, 1615, 1500 cm⁻¹

(38)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-phenyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520, 1495 cm⁻¹

(39)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 153° to 162° C. (dec.).

I.R. (Nujol): 3260, 3160, 1763, 1665, 1608, 1520 cm⁻¹

(40) Pivaloyloxymethyl7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(sym isomer), mp 132° to 135° C. (dec.).

I.R. (Nujol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 cm⁻¹

EXAMPLE 7

To a cold solution of phosphorus pentachloride (2.5 g) in methylenechloride (60 ml) was added2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.54 g) at -15° C. and the mixture was stirred for 45minutes at the same temperature. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(4.0 g) and trimethylsilylacetamide (12 g) in methylene chloride (60 ml)was warmed to make a clear solution and then cooled to -15° C. Thesolution was added to the above activated mixture and the mixture wasstirred for 0.5 at 0° to -5° C. The reaction mixture was poured intocold aqueous solution (150 ml) of sodium bicarbonate (7.1 g) and stirredat ambient temperature for 15 minutes. The aqueous layer was separatedout and added to ethyl acetate. The mixture was adjusted to pH 3 with10% hydrochloric acid and then filtered. The ethyl acetate layer wasseparated from the filtrate, washed with a saturated aqueous solution ofsodium chloride, dried over magnesium sulfate and evaporated to dryness.The residue was triturated with diethyl ether and precipitates werecollected by filtration and then dried to give a crude product (1.8 g).This product was dissolved in an aqueous solution of sodium bicarbonateand the solution was adjusted to pH 3 with 10% hydrochloric acid.Precipitates were collected by filtration, washed with water and thendried to give7-[2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g), mp 155° to 160° C.

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.0-2.50 (4H, m), 3.70 (2H, broad s), 4.30 and4.57 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.27-5.43 (1H, m), 5.80(1H, dd, J=4 and 8 Hz), 5.83-6.20 (2H, m), 8.08 (2H, s), 9.45 (1H, d,J=8 Hz), 9.50 (1H, s).

EXAMPLE 8

To a cold solution of phosphorus pentachloride (2.5 g) in methylenechloride (60 ml) was added2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.54 g) at -15° C. and the mixture was stirred for 30minutes at the same temperature. On the other hand, a mixture of7-amino-3-cephem-4-carboxylic acid (2.2 g) and trimethylsilylacetamide(11 g) in methylene chloride (60 ml) was warmed to make a clear solutionand then cooled to -15° C. To the solution was added the above activatedmixture and the mixture was stirred for 20 minutes at -5° C. Thereaction mixture was poured into cold aqueous solution (150 ml) ofsodium bicarbonate (7 g) and stirred at ambient temperature for an hour.The aqueous layer was separated out and added to ethyl acetate. Themixture was adjusted to pH 3 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate and evaporatedto dryness. Precipitated crystals were collected by filtration, washedsuccessively with ethyl acetate and diethyl ether to give a crudeproduct (1.5 g). This product was dissolved in an aqueous solution ofsodium bicarbonate and the pH was adjusted to 2 with dil. hydrochloricacid. Precipitates were collected by filtration, washed with water andthen dried. The obtained product (1.2 g) was dissolved in aqueousacetone, treated with activated charcoal and then evaporated. Theprecipitates were collected by filtration, washed with water and driedto give7-[2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (0.93 g). mp 180° to 185° C. (dec.).

I.R. (Nujol): 3500, 3430, 3300, 3200, 1770, 1690, 1660, 1640, 1620,1580, 1510 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.87-2.50 (4H, m), 3.60 (2H, broad s), 5.07 (1H,d, J=8 Hz), 5.27-5.50 (1H, m), 5.80 (1H, dd, J=4 and 8 Hz), 5.87-6.23(2H, m), 6.47 (1H, broad s), 8.10 (2H, s), 9.47 (1H, d, J=8 Hz)

EXAMPLE 9

To a cold solution of phosphorus pentachloride (1.25 g) in methylenechloride (30 ml) was added2-(2-cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.34 g) at -15° C. and the mixture was stirred for 30minutes at the same temperature. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.98 g) and trimethylsilylacetamide (6 g) in methylene chloride (30 ml)was warmed to make a clear solution and then cooled to -15° C. Thesolution was added to the above activated mixture and the mixture wasstirred for 0.5 hour at 0° to 5° C. The reaction mixture was poured intocold aqueous solution (100 ml) of sodium bicarbonate (4.03 g) andstirred at ambient temperature for 30 minutes. The aqueous layer wasseparated, added to ethyl acetate, adjusted to pH 4 with 10%hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated to dryness. The residue wastriturated with diethyl ether, collected by filtration and dried to givea crude product (400 mg). This product was dissolved in an aqueoussolution of sodium bicarbonate and the pH was adjusted to 2 withhydrochloric acid. Precipitates were collected by filtration, washedwith water and then dried to give7-[2-(2-cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (250 mg). mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1660, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.17 (6H, m), 3.70 (2H, broad s), 4.33 and4.58 (2H, ABq, J=14 Hz), 4.67-4.83 (1H, m), 5.17 (1H, d, J=4 Hz), 5.83(1H, dd, J=4 and 8 Hz), 5.60-6.12 (2H, m), 8.15 (2H, s) 9.53 (1H, d, J=8Hz), 9.93 (1H, s)

EXAMPLE 10

To a cold solution of phosphorus pentachloride (1.50 g) in methylenechloride (30 ml) was added2-(2-cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.61 g) at -15° C. The mixture was stirred for 30minutes at -13° to -10° C. and evaporated and then to the residue wasadded tetrahydrofuran (20 ml). On the other hand, a mixture of7-amino-3-(tetrazolo]1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (2.86 g), sodium bicarbonate (2.52 g), water (80 ml) and acetone(45 ml) was cooled to 5° to 10° C. To the solution was added the aboveactivated mixture. The mixture was stirred for 20 minutes at 5° to 10°C., allowed to warm to room temperature and then evaporated. To theresidue was added ethyl acetate and the mixture was adjusted to pH 2with 10% hydrochloric acid and then extracted with ethyl acetate. Theextract was treated with activated charcoal (0.5 g), dried overmagnesium sulfate and then evaporated. The residue was triturated withdiethyl ether, collected by filtration to give a crude product (2.37 g).This product was dissolved in an aqueous solution of sodium bicarbonateand the pH was adjusted to 2 with hydrochloric acid. Precipitates werecollected by filtration to give7-[2-(2-cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.28 g), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.40-2.20 (6H, m), 3.73 (2H, broad s), 4.27 and4.65 (2H, ABq, J=13 Hz), 4.65-4.88 (1H, m), 5.18 (1H, d, J=5 Hz), 5.80(1H, dd, J=5 and 8 Hz), 5.78-6.02 (2H, m), 7.80 (1H, d, J=10 Hz), 8.17(2H, broad s), 8.60 (1H, d, J=10 Hz), 9.55 (1H, d, J=8 Hz)

EXAMPLE 11

To a cold solution of phosphorus pentachloride (1.5 g) in methylenechloride (30 ml) was added2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (1.37 g) at -15° C. and the mixture was stirred for 30 minutesat -13° to -10° C. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.18 g) and trimethylsilylacetamide (6 g) in methylene chloride (30 ml)was warmed to make a clear solution and then cooled to -20° C. Thesolution was added to the above activated mixture and the mixture wasstirred for 0.5 hour at -10° C. The reaction mixture was poured into acold saturated aqueous solution (60 ml) of sodium bicarbonate andstirred at ambient temperature for 30 minutes. The aqueous layer wasseparated out, added to ethyl acetate, adjusted to pH 2 to 3 with 10%hydrochloric acid and extracted with ethyl acetate. The extract wasdried over magnesium sulfate and evaporated to dryness. The residue waswashed with diethyl ether to give a crude product (2.62 g). This productwas dissolved in an aqueous solution of sodium bicarbonate and the pHwas adjusted to 2 with hydrochloric acid. Precipitates were collected byfiltration to give7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.22 g). mp 140° to 145° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33-2.10 (8H, m), 3.72 (2H, broad s), 4.33 and4.58 (2H, ABq, J=13 Hz), 4.60-4.90 (1H, m), 5.17 (1H, d, J=5 Hz), 5.82(1H, dd, J=5 and 8 Hz), 8.15 (2H, s), 9.52 (1H, d, J=8 Hz), 9.58 (1H,s).

EXAMPLE 12

To a cold solution of phosphorus pentachloride (1.25 g) in methylenechloride (25 ml) was added2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (1.28 g) at -15° C. and the mixture was stirred for 30 minutesat -13° to -10° C. On the other hand, a mixture of7-amino-3-cephem-4-carboxylic acid (1.1 g), and trimethylsilylacetamide(5.5 g) in methylene chloride (25 ml) was warmed to make a clearsolution and then cooled to -15° C. The solution was added to the aboveactivated mixture and the mixture was stirred for 0.5 hour at -10° C.The reaction mixture was poured into a saturated aqueous solution (55ml) of sodium bicarbonate and stirred at ambient temperature for 30minutes and then evaporated to remove methylene chloride. The residuewas washed with ethyl acetate and to the aqueous layer was added ethylacetate. The mixture was adjusted to pH 3 with 10% hydrochloric acid andextracted with ethyl acetate. The extract was dried over magnesiumsulfate, treated with activated charcoal (1.0 g) and then evaporated.The residue was washed with diethyl ether to give a crude product (1.03g). This product was dissolved in an aqueous solution of sodiumbicarbonate and the solution was adjusted to pH 3 with 10% hydrochloricacid. Precipitates were collected by filtration to give7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (860 mg). mp 170° to 175° C.

I.R. (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635,1625, 1570, 1505 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33-2.07 (8H, m), 3.43-3.77 (2H, m), 4.60-4.93(1H, m), 5.15 (1H, d, J=5 Hz), 5.90 (1H, dd, J=5 and 8 Hz), 6.43-6.67(1H, m), 8.23 (2H, broad s), 9.63 (1H, d, J=8 Hz)

EXAMPLE 13

The following compounds were obtained according to similar manners tothose of Examples 1 to 3, 5 and 7 to 12.

(1)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 154° to 159° C. (dec.).

I.R. (Nujol) 3300, 1770, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.0 (3H, s), 2.0-2.40 (4H, m), 3.52 (2H, broad s),4.70 and 4.97 (2H, ABq, J=14 Hz), 5.12 (1H, d, J=4 Hz), 5.27-5.40 (1H,m), 5.82 (1H, dd, J=4 and 8 Hz), 5.83-6.17 (2H, m), 8.13 (2H, s), 9.50(1H, d, J=8 Hz)

(2)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.90-2.30 (4H, m), 3.62 (2H, broad s), 3.88 (3H,s), 4.25 (2H, broad s), 5.07 (1H, d, J=4 Hz), 5.20-5.40 (1H, m), 5.80(1H, dd, J=4 and 8 Hz), 5.83-6.17 (2H, m), 8.08 (2H, s), 9.47 (1H, d,J=8 Hz)

(3)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720. 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.83-2.50 (4H, m), 3.67 (2H, broad s), 4.27 and4.48 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=4 Hz), 5.30 (2H, s), 5.27-5.50(1H, m), 5.82 (2H, dd, J=4 and 8 Hz), 5.83-6.20 (2H, m), 8.17 (2H, s),9.50 (1H, d, J=8 Hz)

(4)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.90-2.50 (4H, m), 2.97 (2H, t, J=6 Hz), 3.73 (2H,broad s), 4.30 and 4.50 (2H, ABq, J=14 Hz), 4.52 (2H, t, J=6 Hz), 5.20(1H, d, J=4 Hz), 5.30-5.57 (1H, m), 5.90 (1H, dd, J=4 and 8 Hz),5.93-6.33 (2H, m), 8.33 (2H, s), 9.77 (1H, d, J=8 Hz)

(5)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.93-2.33 (4H, m), 3.60 (2H, broad s), 4.22 and4.37 (2H, ABq, J=13 Hz), 4.83-5.0 (2H, m), 5.0-5.40 (4H, m), 5.60-6.17(4H, m), 8.07 (2H, s), 9.47 (1H, d, J=8 Hz)

(6)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1615, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.90-2.43 (4H, m), 3.68 (2H, broad s), 4.22 and4.58 (2H, ABq, J=13 Hz), 5.10 (1H, d, J=5 Hz), 5.20-5.47 (1H, m), 5.78(1H, dd, J=5 and 8 Hz), 5.80-6.20 (2H, m), 7.75 (1H, d, J=10 Hz), 8.13(2H, broad s), 8.55 (1H, d, J=10 Hz), 9.52 (1H, d, J=8 Hz)

(7)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 95° to 100° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.40 (9H, s), 2.07-2.50 (4H, m), 3.30-3.57 (2H,m), 3.67-3.87 (2H, m), 4.27-4.57 (4H, m), 5.17 (1H, d, J=5 Hz),5.23-5.57 (1H, m), 5.70-6.30 (3H, m), 8.17 (2H, broad s), 9.53 (1H, d,J=8 Hz)

(8)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.13 (6H, m), 3.63 (2H, broad s), 4.60-4.83(1H, m), 5.12 (1H, d, J=4 Hz), 5.77-6.0 (3H, m), 6.50 (1H, t, J=3Hz),8.15 (2H, s), 9.55 (1H, d, J=8 Hz)

(9)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.10 (6H, m), 2.07 (3H, s), 3.60 (2H, broads), 4.67-4.83 (1H, m), 4.77 and 5.03 (2H, ABq, J=14 Hz), 5.17 (1H, d,J=4 Hz), 5.77-6.10 (3H, m), 8.17 (2H, s), 9.60 (1H, d, J=8 Hz)

(10)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 173° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.17 (6H, m), 3.16 (2H, broad s), 3.93 (3H,s), 4.30 (2H, broad s), 4.55-4.80 (1H, m), 5.10 (1H, d, J=4 Hz), 5.80(1H, dd, J=4 and 8 Hz), 5.80-5.93 (2H, m), 8.08 (2H, s), 9.50 (1H, d,J=8 Hz)

(11)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.27 (6H, m), 3.75 (2H, broad s), 4.30 and4.55 (2H, ABq, J=14 Hz), 4.67-4.83 (1H, m), 5.17 (1H, d, J=4 Hz), 5.37(2H, s), 6.17-5.77 (3H, m), 8.18 (2H, s), 9.57 (1H, d, J=8 Hz)

(12)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C.

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.17 (6H, m), 3.77 (2H, broad s), 4.37 and4.50 (2H, ABq, J=14 Hz), 4.53 (2H, t, J=6 Hz), 4.67-4.93 (1H, m), 5.23(1H, d, J=4 Hz), 5.93 (1H, dd, J=4 and 8 Hz), 5.97-6.17 (2H, m), 8.70(2H, s), 9.80 (1H, d, J=8 Hz)

(13)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.16 (6H, m), 3.66 (2H, broad s), 4.25 and4.43 (2H, ABq, J=14 Hz), 4.55-4.80 (1H, m), 4.93-5.0 (2H, m), 5.10 (1H,d, J=4 Hz), 5.20-5.37 (2H, m), 5.67-6.20 (4H, m), 8.08 (2H, s), 9.50(1H, d, J=8 Hz)

(14)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 100° to 105° C. (dec.).

I.R. (Nujol): 3300, 3170, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.37 (9H, s), 1.50-2.20 (8H, m), 2.92 (2H, t, J=6Hz), 3.68 (2H, broad s), 4.07-4.47 (4H, m), 4.53-4.83 (1H, m), 5.10 (1H,d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 5.70-5.93 (2H, m), 8.10 (2H,broad s), 9.47 (1H, d, J=8 Hz)

(15)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 140° to 145° C. (dec.).

I.R. (Nujol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33-2.17 (8H, m), 2.03 (3H, s), 3.57 (2H, broads), 4.60-4.90 (1H, m), 4.73 and 4.97 (2H, ABq, J=13 Hz), 5.15 (1H, d,J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 8.10 (2H, broad s), 9.47 (1H, d,J=8 Hz)

(16)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400,3290, 3180, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33-2.07 (8H, m), 3.70 (2H, broad s), 3.93 (3H,s), 4.32 (2H, broad s), 4.10-4.90 (1H, m), 5.12 (1H, d, J=5 Hz), 5.78(1H, dd, J=5 and 8 Hz), 8.10 (2H, broad s), 9.47 (1H, d, J=8 Hz)

(17)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155°-160° C. (dec.).

I.R. (Nujol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.27-2.07 (8H, m), 3.70 (2H, broad s), 4.28 and4.53 (2H, ABq, J=13 Hz), 4.70-4.93 (1H, m), 5.17 (1H, d, J=5 Hz), 5.33(2H, s), 5.85 (1H, dd, J=5 and 8 Hz), 8.23 (2H, broad s), 9.60 (1H, d,J=8 Hz)

(18)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.30-2.10 (8H, m), 3.73 (2H, broad s), 4.32 and4.50 (2H, ABq, J=13 Hz), 4.60-4.90 (1H, m), 4.83-5.17 (2H, m), 5.17 (1H,d, J=5 Hz), 5.17-5.50 (2H, m), 5.87 (1H, dd, J=5 and 8 Hz), 5.67-6.33(1H, m), 8.20 (2H, broad s), 9.60 (1H, d, J=8 Hz)

(19)7[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 160° to 165° C. (dec.).

I.R. (Nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580,1540, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.40-2.03 (8H, m), 3.78 (2H, broad s), 4.27 and4.65 (2H, ABq, J=13 Hz), 4.67-4.93 (1H, m), 5.20 (1H, d, J=5 Hz), 5.87(1H, dd, J=5 and 8 Hz), 7.78 (1H, d, J=10 Hz), 8.15 (2H, broad s), 8.58(1H, d, J=10 Hz), 9.53 (1H, d, J=8 Hz)

(20)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-methoxycarbonylethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 125° to 130° C. (dec.).

I.R. (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.30-2.07 (8H, m), 2.80-3.20 (2H, m), 3.58 (3H,s), 3.67 (2H, broad s), 4.20-4.70 (4H, m), 4.60-4.90 (1H, m), 5.12 (1H,d, J=5 Hz), 5.78 (1H, dd, J=5 and 8 Hz), 8.07 (2H, broad s), 9.43 (1H,d, J=8 Hz)

(21)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). pale yellow powder. mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1710-1670, 1590, 1520, 1240, 1170, 1090,1000, 720 cm⁻¹

(22)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). white powder. mp 150° to 154° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160,1060, 1000 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50 (8H, m), 1.82 (4H, m), 3.54 and 3.76 (2H,ABq, J=20 Hz), 4.32 (1H, m), 4.24 and 4.60 (2H, ABq, J=14 Hz), 5.10 (1H,d, J=5 Hz), 5.74 (1H, dd, J=5 and 8 Hz), 8.02 (2H, m), 9.48 (1H, s),9.38 (1H, d, J=8 Hz)

(23)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). white powder. mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240,1160, 1000, 980, 730 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50 (8H, m), 1.85 (4H, m), 3.60 (2H, m), 4.0-4.50(1H, m), 5.13 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 6.50 (1H,m), 8.13 (2H, m), 9.37 (1H, d, J=8 Hz)

(24)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer). mp 230° to 235° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm⁻¹

(25)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). pale brown powder.

I.R. (Nujol): 3300, 1770, 1670, 1520, 1240, 1160, 1000 cm⁻¹

(26)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1620, 1525 cm⁻¹

(27)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-morpholinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 183° to 188° C. (dec.).

I.R. (Nujol): 3300,3150, 1770, 1670, 1610, 1530 cm⁻¹

(28)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.).

I.R. (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 cm⁻¹

(29)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). white powder. mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180, 1000 cm⁻¹

(30)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 185° to 190° C. (dec.).

I.R. (Nujol): 3280, 3150, 1760, 1665, 1620, 1520 cm⁻¹

(31)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-piperidinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 230° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1600, 1520 cm⁻¹

EXAMPLE 14

A mixture of7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.5 g), tetrazolo[1,5-b]pyridazine-6-thiol (1.35 g)and sodium bicarbonate (1.1 g) in pH 6.8 phosphate buffer solution (130ml) was stirred for 2 hours at 70° C. The reaction mixture was cooled inan ice bath, mixed with ethyl acetate and adjusted to pH 3 with 10%hydrochloric acid. An insoluble material was filtered off and thefiltrate was extracted with ethyl acetate. The extract was dried overmagnesium sulfate and evaporated to dryness. The residue was trituratedwith diethyl ether to give7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.7 g), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1615, 1585, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.77 (2H, broad s), 4.23 and 4.63 (2H, ABq, J=13Hz), 5.23 (1H, d, J=4 Hz), 5.93 (1H, dd, J=4 and 8 Hz), 7.00-7.50 (5H,m), 7.77 (1H, d, J=10 Hz), 8.30 (2H, s), 8.60 (1H, d, J=10 Hz), 9.85(1H, d, J=8 Hz)

EXAMPLE 15

A mixture of7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (4.0 g),1-[2-(N-t-butoxycarbonylamino)ethyl]-1H-tetrazole-5-thiol (2.45 g) andsodium bicarbonate (1.3 g) in pH 6.8 phosphate buffer solution (150 ml)was stirred for 1.5 hours at 70° C. The reaction mixture was cooled inan ice bath, mixed with ethyl acetate and adjusted to pH 3 with 10%hydrochloric acid. An insoluble material was filtered off and thefiltrate was extracted with ethyl acetate. The extract was dried overmagnesium sulfate and evaporated to dryness. The residue was trituratedwith diethyl ether to give7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.27 (9H, s), 3.3-3.5 (2H, m), 3.70 (2H, broad s),4.3-4.6 (4H, m), 5.18 (1H, d, J=4 Hz), 5.90 (1H, dd, J=4 and 8 Hz),7.0-7.5 (5H, m), 8.28 (2H, s), 9.88 (1H, d, J=8 Hz)

EXAMPLE 16

A mixture of7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (3.3 g), 1-allyl-1H-tetrazole-5-thiol (1.4 g) andsodium bicarbonate (1.3 g) in pH 6.8 phosphate buffer solution (210 ml)was stirred 2 hours at 70° C. The reaction mixture was cooled in an icebath, mixed with ethyl acetate and adjusted to pH 2 with 10%hydrochloric acid. An insoluble material was filtered off and thefiltrate was extracted with ethyl acetate. The extract was dried overmagnesium sulfate and evaporated to dryness. The residue was trituratedwith diethyl ether to give7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.1 g), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.68 (2H, broad s), 4.28 and 4.45 (2H, ABq, J=13Hz), 4.60-4.83 (2H, m), 4.93-5.07 (2H, m), 5.12 (1H, d, J=4 Hz),5.17-5.57 (4H, m), 5.83 (1H, dd, J=4 and 8 Hz), 5.77-6.37 (2H, m), 8.22(2H, s), 9.67 (1H, d, J=8 Hz)

EXAMPLE 17

A mixture of7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer) (5.1 g), sodium bicarbonate (840 mg), water (50 ml),potassium thiocyanate (24.3 g) and isonicotinamide (1.83 g) was stirredfor 22 hours at 50° to 55° C. The reaction mixture was cooled and addedto ethyl acetate. The mixture was adjusted to pH 2 with 10% hydrochloricacid and filtered. The aqueous layer was separated from the filtrate,washed with ethyl acetate and evaporated. The residue was subjected tocolumn chromatography (non-ionic adsorption resin, Diaion HP20 preparedby Mitsubishi Chemical Industries) and the column was washed with water(0.7 l) and then eluted with 30% aqueous methanol (0.7 l). The eluatescontaining the object compound were collected, washed with ethyl acetateand then evaporated. The residue was lyophilized to giveN-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer) (1.0 g), mp 230° to 235° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.30-1.95 (8H, m), 3.15 and 3.50 (2H, ABq, J=18Hz), 5.60-5.75 (1H, m), 5.06 (1H, d, J=4 Hz), 5.30 and 5.65 (2H, ABq,J=14 Hz), 5.70 (1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 8.45 (2H, d, J=6Hz), 9.42 (2H, d, J=6 Hz), 9.50 (1H, d, J=8 Hz)

EXAMPLE 18

The following compounds were obtained according to similar manners tothose of Examples 14 to 17.

(1)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.73 (2H, broad s), 4.27 and 4.63 (2H, ABq, J=14Hz), 4.60-4.83 (2H, m), 5.18 (1H, d, J=4 Hz), 5.23-5.53 (2H, m), 5.83(1H, dd, J=4 and 8 Hz), 5.87-6.33 (1H, m), 7.82 (1H, d, J=10 Hz), 8.20(2H, s), 8.68 (1H, d, J=10 Hz), 9.68 (1H, d, J=8 Hz)

(2)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), powder.

(3)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3180, 1760, 1670, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.60 (2H, broad s), 4.05 and 4.28 (2H, ABq, J=13Hz), 4.57 (2H, s), 4.73 and 4.95 (2H, ABq, J=9 Hz), 5.07 (1H, d, J=5Hz), 5.73 (1H, dd, J=5 and 8 Hz), 8.17 (2H, broad s), 9.63 (1H, d, J=8Hz)

(4)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

I.R. (Nujol): 3420, 3300, 3190, 1770, 1705, 1670, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.60 and 3.80 (2H, ABq, J=18 Hz), 4.23 and 4.58(2H, ABq, J=13 Hz), 4.67 and 4.87 (2H, ABq, J=9 Hz), 5.13 (1H, d, J=5Hz), 5.82 (1H, dd, J=5 and 8 Hz), 7.72 (1H, d, J=10 Hz), 8.17 (2H, broads), 8.55 (1H, d, J=10 Hz), 9.68 (1H, d, J=8 Hz)

(5)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale brown powder.

I.R. (Nujol): 3300, 1770, 1670, 1520, 1240, 1160, 1000 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.33 (9H, s), 1.40-2.07 (10H, m), 2.95 (2H, m),3.63 (2H, m), 4.0-4.43 (4H, m), 4.70 (1H, m), 5.07 (1H, d, J=5 Hz), 5.73(1H, dd, J=5 and 8 Hz), 6.80 (1H, m), 8.07 (2H, m), 9.89 (1H, d, J=8 Hz)

(6)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 178° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-2.00 (8H, m), 3.67 (2H, broad s), 4.34 and4.60 (2H, ABq, J=14 Hz), 4.67-4.83 (1H, m), 5.17 (1H, d, J=4 Hz), 5.82(1H, dd, J=4 and 8 Hz), 8.12 (2H, s), 8.73 (1H, s), 9.50 (1H, d, J=8 Hz)

(7)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-morpholinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 188° C. (dec.).

I.R. (Nujol): 3300, 3150, 1770, 1670, 1610, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.50-1.90 (8H, m), 2.00-2.27 (2H, m), 2.50-2.83(6H, m), 3.50-3.83 (6H, m), 4.23-4.53 (4H, m), 4.70-4.86 (1H, m), 5.13(1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.50 (1H, d,J=8 Hz)

(8)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g), mp 155° to 160° C.

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620 1520 cm⁻¹

(9)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

(10)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(11)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(12)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

(13)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1615, 1520 cm⁻¹

(14)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 95° to 100° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1680, 1620, 1520 cm⁻¹

(15)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C.

I.R. (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 cm⁻¹

(16)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1660, 1620, 1520 cm⁻¹

(17)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1670, 1620, 1520 cm⁻¹

(18)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 173° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm⁻¹

(19)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 cm⁻¹

(20)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-{1-(2-carboxyethyl)-1H-tetrazol-5-yl}thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C.

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(21)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1680, 1620, 1520 cm⁻¹

(22)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 100° to 105° C. (dec.).

I.R. (Nujol): 3300, 3170, 1770, 1670, 1620, 1520 cm⁻¹

(23)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3280, 3150, 1760, 1665, 1620, 1520 cm⁻¹

(24)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

(25)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3290, 3180, 1770, 1670, 1620, 1520 cm⁻¹

(26)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520 cm⁻¹

(27)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer); mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1620, 1520 cm⁻¹

(28)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580,1540, 1520 cm⁻¹

(29)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180, 1000 cm⁻¹

(30)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-methoxycarbonylethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 cm⁻¹

(31)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), yellow powder, mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1710-1670, 1590, 1520, 1240, 1170, 1090,1000, 720 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.3-2.1 (8H, m), 3.32 (3H, s), 3.66 (2H, m), 4.11(2H, m), 4.76 (1H, m), 5.16 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8Hz), 8.13 (2H, broad s), 9.50 (1H, d, J=8 Hz), 12.50 (1H, broad s)

(32)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 150° to 154° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160,1060, 1000 cm⁻¹

(33)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-piperidinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 230° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1600, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.3-2.0 (6H, m), 2.10-2.3 (2H, m), 2.73-3.10 (6H,m), 3.57 (2H, broad s), 4.10-4.50 (4H, m), 4.60-4.80 (1H, m), 5.00 (1H,d, J=4 Hz), 5.67 (1H, dd, J=4 and 8 Hz), 9.06 (2H, s), 9.37 (1H, d, J=8Hz)

EXAMPLE 19

A solution of 4-nitrobenzyl7-[2-(3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer) (4.4 g) in a mixture of tetrahydrofuran (80 ml), water (50ml) and acetic acid (4.4 ml) was hydrogenated over 10%palladium-charcoal (2.2 g) at atmospheric pressure at room temperaturefor 3 hours. The catalyst was filtered and washed with tetrahydrofuran.The filtrate and washing were combined and then evaporated. To theresidue were added ethyl acetate and an aqueous solution of sodiumbicarbonate so that the pH was adjusted to 8. The aqueous layer wasseparated, adjusted to pH 1 to 2, and extracted with ethyl acetate. Theextract was washed successively with water and an aqueous solution ofsodium chloride, treated with activated charcoal, dried over magnesiumsulfate and then evaporated. The residue was washed with diethyl etherto give a yellow powder (1.0 g). Water (10 ml) was added to this crudeproduct and the mixture was stirred for 30 minutes. The precipitateswere collected by filtration, washed with water and dried under reducedpressure to give a yellow powder of7-[2-(3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (1.0 g), decomposed by 193° C.

I.R. (Nujol): 3450, 3320, 3200, 1770, 1710, 1665, 1630, 1560, 1515,1325, 1170, 1110, 940 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, m), 5.21 (1H, d, J=5 Hz), 5.94 (1H, dd,J=5 and 8 Hz), 6.48 (1H, m), 7.53 (4H, broad s), 8.27 (2H, broad s),9.87 (1H, d, J=8 Hz)

EXAMPLE 20

A solution of 4-nitrobenzyl7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer)(4.5 g) in a mixture of tetrahydrofuran (45 ml) and water(20 ml) was hydrogenated over 10% palladium-charcoal (2.5 g) for 3 hoursat atmospheric pressure at room temperature. The catalyst was filteredand the filtrate was evaporated. To the residue was added ethyl acetateand the mixture was adjusted to pH 8 with an aqueous solution of sodiumbicarbonate. The aqueous layer was separated and thereto was added ethylacetate, and then the pH was adjusted to 3 with hydrochloric acid. Theresulting mixture was extracted with ethyl acetate and the extract waswashed with water, dried over magnesium sulfate and then evaporated togive7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-cephem-4-carboxylicacid (syn isomer) (1.4 g), mp 168° to 170° C. (dec.).

I.R. (Nujol): 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540 cm⁻¹

N.M.R. (DMSO-d₆, δ): 3.58 (2H, broad s), 5.15 (1H, d, J=4 Hz), 5.90 (1H,dd, J=4 and 8 Hz), 6.47 (1H, t, J=3 Hz), 6.97-7.60 (5H, m), 8.27 (2H,s), 9.92 (1H, d, J=8 Hz)

EXAMPLE 21

The following compounds were obtained according to similar manners tothose of Examples 19 and 20.

(1)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer).

I.R. (Nujol): 3300-3100, 1780, 1690-1660, 1520, 1270 cm⁻¹

(2)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3260, 3180, 1775, 1675, 1625, 1600, 1520, 1480 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad s), 5.20 (1H, d, J=5 Hz), 5.93(1H, dd, J=5 and 8 Hz), 6.52 (1H, t, J=4 Hz), 7.33 (2H, d, J=9 Hz), 7.47(2H, d, J=9 Hz), 8.32 (2H, broad s), 9.90 (1H, d, J=8 Hz)

(3)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

I.R. (Nujol): 3400, 3270, 3180, 1765, 1675, 1605, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad s), 5.22 (1H, d, J=5 Hz), 5.97(1H, dd, J=5 and 8 Hz), 6.53 (1H, t, J=4 Hz), 7.25 (2H, s), 7.37 (2H,s), 8.30 (2H, broad s), 9.90 (1H, d, J=8 Hz)

(4)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

N.M.R. (d₆ -DMSO, δ): 3.53 (2H, d, J=4 Hz), 4.60-4.77 (2H, m), 5.07 (1H,d, J=4 Hz), 5.0-5.50 (2H, m), 5.83 (1H, dd, J=4 and 8 Hz), 5.70-6.23(1H, m), 6.45 (1H, t, J=4 Hz), 8.13 (2H, s), 9.57 (1H, d, J=8 Hz)

(5)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C.

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

(6)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3500, 3430, 3300, 3200, 1770, 1690, 1660, 1640, 1620,1580, 1510 cm⁻¹

(7)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 154° to 159° C. (dec.).

I.R. (Nujol): 3300, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(8)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

(9)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(10)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(11)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 1770, 1670, 1620, 1520 cm⁻¹

(12)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1615, 1520 cm⁻¹

(13)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 95° to 100° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1680, 1620, 1520 cm⁻¹

(14)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 cm⁻¹

(15)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1660, 1620, 1520 cm⁻¹

(16)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm⁻¹

(17)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1670, 1620, 1520 cm⁻¹

(18)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1720, 1670, 1620, 1520 cm⁻¹

(19)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 173° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm⁻¹

(20)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1650, 1620, 1520 cm⁻¹

(21)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C.

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(22)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1680, 1620, 1520 cm⁻¹

(23)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 100° to 105° C. (dec.).

I.R. (Nujol): 3300, 3170, 1770, 1670, 1620, 1520 cm⁻¹

(24)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3280, 3150, 1760, 1665, 1620, 1520 cm⁻¹

(25)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

(26)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C.

I.R. (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635,1625, 1570, 1505 cm⁻¹

(27)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3480, 3370, 3250, 1785, 1730, 1680, 1630, 1530 cm⁻¹

(28)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3290, 3180, 1770, 1670, 1620, 1520 cm⁻¹

(29)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3400, 3290, 3180, 1765, 1720, 1670, 1620, 1520 cm⁻¹

(30)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3300, 3190, 1770, 1670, 1620, 1520 cm⁻¹

(31)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3570, 3440, 3320, 3180, 1775, 1710, 1660, 1620, 1580,1540, 1520 cm⁻¹

(32)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale brown powder.

I.R. (Nujol): 3300, 1770, 1670, 1520, 1240, 1160, 1000 cm⁻¹

(33)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180, 1000 cm⁻¹

(34)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-methoxycarbonylethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3480, 3370, 3250, 1780, 1740, 1685, 1625, 1530 cm⁻¹

(35)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), yellow powder, mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1710-1670, 1590, 1520, 1240, 1170, 1090,1000, 720 cm⁻¹

(36)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp 230° to 235° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1610, 1560, 1520, 1510 cm⁻¹

(37)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 178° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1620, 1525 cm⁻¹

(38)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-morpholinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 188° C. (dec.).

I.R. (Nujol): 3300, 3150, 1770, 1670, 1610, 1530 cm⁻¹

(39)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 150° to 154° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1400, 1240, 1160,1060, 1000 cm⁻¹

(40)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240,1160, 1000, 980, 730 cm⁻¹

(41)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-piperidinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 230° C. (dec.).

I.R. Nujol: 3300, 3200, 1770, 1670, 1600, 1520 cm⁻¹

EXAMPLE 22

A solution of7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g) in formic acid (14 ml) was stirred at ambienttemperature for 3 hours and evaporated to dryness. The residue wasdissolved in a mixture of ethyl acetate and an aqueous solution ofsodium bicarbonate and adjusted to pH 2 with 10% hydrochloric acid. Theaqueous layer was separated out, washed with ethyl acetate andconcentrated to remove ethyl acetate. The aqueous solution was subjectedto column chromatography on Diaion HP-20 resin (Trademark: prepared byMitsubishi Chemical Industries Ltd.). After the column was washed withwater, elution was carried out with 50% aqueous methanol. The eluent wasevaporated to remove methanol under reduced pressure and the resultantaqueous solution was lyophilized to give7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.3 g), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3250, 1760, 1670, 1620, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.40 (2H, broad s), 3.60 (2H, broad s), 4.23 (2H,broad s), 4.60 (2H, broad s), 5.13 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4and 8 Hz), 7.0-7.5 (5H, m), 8.33 (2H, s), 9.90 (1H, d, J=8 Hz)

EXAMPLE 23

A solution of7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)(4.0 g) informic acid (40 ml) was stirred for 2.5 hoursat ambient temperature. The reaction mixture was evaporated and driedunder reduced pressure to give oil. To the oil were added water (40 ml)and 1 N hydrochloric acid (5 ml) to give clear solution. The solutionwas subjected to column chromatography on Diaion HP-20 resin (Trademark:prepared by Mitsubishi Chemical Industries Ltd.) and eluted successivelywith water and 5% aqueous methanol to give7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.95 g), mp 184° to 196° C. (dec.).

I.R. (Nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.9 (2H, m), 2.8 (2H, m), 3.3 (2H, m), 3.5(2H, m), 4.1 (4H, m), 4.5 (2H, m), 4.90 (1H, d, J=5 Hz), 5.56 (1H, d,J=5 Hz)

EXAMPLE 24

A solution of7-[2-{2-(N-t-butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.9 g) in formic acid (28 ml) was stirred for 2 hoursat ambient temperature. The reaction mixture was post-treated in aconventional manner to give7-[2-(2-aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.55 g), mp 190° to 198° C. (dec.).

I.R. (Nujol): 3250, 3160, 1760, 1650, 1615, 1522, 1020 cm⁻¹

N.M.R. (DCl, δ): 3.11 (2H, broad s), 3.28-3.65 (2H, m), 4.35 (2H, broads), 4.48-4.78 (2H, m), 5.25 (1H, d, J=4.5 Hz), 5.42 (2H, s), 5.88 (1H,d, J=4.5 Hz)

EXAMPLE 25

A mixture of7-[2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylaminoethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (3.5 g) and formic acid (35 ml) was stirred for 2hours at room temperature. The reaction mixture was evaporated and theresidue was washed successively with diethyl ether and acetone. Thewashed residue (2.65 g) was added to an aqueous solution of sodiumbicarbonate (60 ml.). The mixture was stirred and then filtered toseparate insoluble materials. To the filtrate was added ethyl acetateand the mixture was adjusted to pH 3 with 3% hydrochloric acid and thenthe aqueous layer was separated. On the other hand, to the filteredmaterials obtained above were added water and ethyl acetate. The mixturewas adjusted to pH 3 with 10% hydrochloric acid and then the aqueouslayer was separated. The separated aqueous layers were combined,adjusted to pH 2 with 10% hydrochloric acid, washed with ethyl acetateand evaporated to remove ethyl acetate. The residue was subjected tocolumn chromatography (non ionic adsorption resin, Diaion HP-20 preparedby Mitsubishi Chemical Industries), eluting with water, 30% methanol,50% methanol and 100% methanol. The fractions containing the objectcompound were collected, evaporated and then lyophilized to give7-[2-(2-cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (580 mg), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3400, 3300, 3170, 1760, 1665, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.87-2.52 (4H, m), 3.27-3.73 (4H, m), 4.13-4.37(2H, m), 4.57-4.80 (2H, m), 5.03 (1H, d, J=5 Hz), 5.27-5.53 (1H, m),5.70 (1H, d, J=5 Hz), 5.85-6.27 (2H, m)

EXAMPLE 26

The following compounds were obtained according to similar manners tothose of Examples 22 to 25.

(1)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 195° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1575, 1520, 1400 cm⁻¹

N.M.R. (D₂ O+DCl, δ): 1.55 (3H, d, J=7 Hz), 3.5 (2H, t, J=4.6 Hz),3.7-4.2 (1H, m), 4.67 (2H, t, J=4.6 Hz), 5.27 (1H, d, J=4.5 Hz), 6.03(1H, d, J=4.5 Hz), 6.90 (1H, d, J=6 Hz)

(2)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 182° to 187° C. (dec.).

I.R. (Nujol): 3260, 3150, 1758, 1660, 1616, 1575, 1520, 1400 cm⁻¹

N.M.R. (DCl+D₂ O, δ): 1.55 (3H, d, J=6.5 Hz), 1.93-2.50 (2H, m), 3.25(2H, t, J=7 Hz), 3.70-4.15 (1H, m), 4.5 (2H, t, J=6 Hz), 5.23 (1H, d,J=4.5 Hz), 6.05 (1H, d, J=4.5 Hz), 6.88 (1H, d, J=6 Hz)

(3)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 195° C. (dec.).

I.R. (Nujol): 3300-3100, 1770-1740, 1660, 1620, 1570, 1520, 1280, 1170,1060, 1020 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.87 (3H, s), 1.9 (2H, m), 2.9 (2H, m), 3.2(2H, m), 4.2 (2H, m), 4.93 (1H, d, J=5 Hz), 5.60 (1H, d, J=5 Hz)

(4)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 205° C. (dec.).

I.R. (Nujol): 3400-3150, 1760, 1660, 1630-1590, 1520, 1340, 1170, 1030cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.00 (2H, m), 2.90 (2H, m), 3.33 and 3.83 (2H,ABq, J=16 Hz), 4.20 (2H, m), 5.09 (1H, d, J=5 Hz), 5.60 (1H, m), 8.15(2H, m), 9.50 (1H, m)

(5)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 182° to 187° C. (dec.).

I.R. (Nujol): 3350, 3150, 1760, 1660, 1625, 1565, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.2-3.9 (6H, m), 4.05,4.32 (2H, ABq, J=14 Hz),4.4-5.0 (4H, m), 5.22 (11H, d, J=4.5 Hz)

(6)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3170, 1760, 1670, 1615 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.17-3.83 (4H, m), 4.28 (2H, broad s), 4.47-4.93(4H, m), 5.10 (1H, d, J=5 Hz), 5.73 (1H, dd, J=5 and 8 Hz), 8.20 (2H,broad s), 9.65 (1H, d, J=8 Hz)

(7)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), white powder, mp 195° to 199° C. (dec.).

I.R. (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1280, 1180, 1000 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.70 (8H, m), 2.20 (2H, m), 2.87 (2H, m), 3.57(2H, m), 4.03-4.60 (4H, m), 4.70 (1H, m), 5.00 (1H, d, J=5 Hz), 5.63(1H, dd, J=5 and 8 Hz), 8.10 (2H, m), 9.40 (1H, d, J=8 Hz)

(8)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3280, 3150, 1760, 1665, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.47-2.30 (8H, m), 2.73-3.13 (2H, m), 3.63 (2H,broad s), 4.17-4.60 (4H, m), 4.60-4.90 (1H, m), 5.03 (1H, d, J=5 Hz),5.73 (1H, dd, J=5 and 8 Hz), 5.75-5.99 (2H, m), 8.13 (2H, broad s), 9.43(1H, d, J=8 Hz)

EXAMPLE 27

A mixture of7-[2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.6 g.), trifluoroacetic acid (10 ml) and anisole (2ml) was stirred for 30 minutes at ambient temperature. The reactionmixture was evaporated and the residue was pulverized with diethylether, collected by filtration and then dried. The obtained product (1.6g) was dissolved in an aqueous solution of sodium bicarbonate, washedwith ethyl acetate and then added to ethyl acetate. The mixture wasadjusted to pH 2 with 1 N hydrochloric acid and extracted with ethylacetate. The extract was washed with a saturated aqueous solution ofsodium chloride, dried over magnesium sulfate and then evaporated. Theresidue was pulverized with diethyl ether, collected by filtration anddried to give7-[2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.52 g), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.67 (2H, broad s), 4.55 (2H, ABq, J=13 Hz), 4.63(2H, s), 5.12 (1H, d, J=4 Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.15 (2H,s), 9.55 (1H, d, J=8 Hz), 9.58 (1H, s).

EXAMPLE 28

The following compounds were obtained according to a similar manner tothat of Example 27.

(1)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.30 and 4.47 (2H, ABq, J=13Hz), 4.68 (2H, s), 4.83-5.15 (2H, m), 5.15 (1H, d, J=5 Hz), 5.17-5.50(2H, m), 5.85 (1H, dd, J=5 and 8 Hz), 5.60-6.20 (1H, m), 8.13 (2H, broads), 9.53 (1H, d, J=8 Hz)

(2)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 160° to 165° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.10 (3H, s), 3.60 (2H, broad s), 4.70 (2H, s),4.77 and 5.03 (2H, ABq, J=14 Hz), 5.20 (1H, d, J=4 Hz), 5.88 (1H, dd,J=4 and 8 Hz), 8.18 (2H, s), 9.57 (1H, d, J=8 Hz)

(3)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.75 (2H, broad s), 4.28 and 4.60 (2H, ABq, J=13Hz), 4.67 (2H, s), 5.17 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz),7.77 (1H, d, J=10 Hz), 8.17 (2H, broad s), 8.60 (1H, d, J=10 Hz), 9.57(1H, d, J=8 Hz)

(4)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3250, 1755, 1660, 1590, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.23-3.67 (4H, m), 4.07 and 4.35 (2H, ABq, J=13Hz), 4.23-4.80 (4H, m), 5.03 (1H, d, J=5 Hz), 5.70 (1H, dd, J=5 and 8Hz), 8.15 (2H, broad s), 11.03 (1H, d, J=8 Hz)

(5)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-phenyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520, 1495 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.65 (2H, broad s), 4.28 and 4.52 (2H, ABq, J=13Hz), 4.63 (2H, s), 5.07 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz),7.63 (5H, s), 8.10 (2H, broad s), 9.47 (1H, d, J=8 Hz)

EXAMPLE 29

A mixture of7-[2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (4.5 g), conc.hydrochloric acid (4.5 ml) and methanol(45 ml) was stirred for 7 hours at ambient temperature. Methanol wasdistilled off from the reaction mixture and the residue was adjusted topH 5 by adding ethyl acetate and an aqueous solution of sodiumbicarbonate. To the separated aqueous layer was added ethyl acetate andthe mixture was adjusted to pH 2 with 10% hydrochloric acid. Theseparated ethyl acetate layer was dried over magnesium sulfate andevaporated in vacuo to a volume of 10 ml. Precipitates were collected byfiltration, washed with ethyl acetate and diethyl ether and dried togive7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.4 g), mp 153° to 162° C. (dec.).

I.R. (Nujol): 3260, 3160, 1763, 1665, 1608, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.67 (3H, s), 3.67 (2H, broad s), 4.23 and 4.53(2H, ABq, J=13 Hz), 5.12 (1H, d, J=4.5 Hz), 5.82 (1H, dd, J=4.5 and 8.5Hz), 7.98 (2H, broad s), 9.37 (1H, d, J=8.5 Hz)

EXAMPLE 30

A solution of7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (257.3 mg) and sodium bicarbonate (42 mg) in water (10ml) was lyophilized. The obtained product was dissolved inN,N-dimethylformamide (5 ml) and to the solution was added a solution ofiodomethyl pivalate (142.5 mg) in N,N-dimethylformamide (1 ml) withstirring and the stirring was continued for 20 minutes. The reactionmixture was washed with water (×3), dried over magnesium sulfate andevaporated. The residue was pulverized with diethyl ether to givepivaloyloxymethyl7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer) (240 mg), mp 132° to 135° C. (dec.).

I.R. (Nujol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.09 (9H, s), 2.70 (3H, s), 3.66 and 3.82 (2H,ABq, J=15 Hz), 4.18 and 4.58 (2H, ABq, J=14 Hz), 5.20 (1H, d, J=4.5 Hz),5.80-6.2 (3H, m), 8.04 (2H, broad s), 9.47 (1H, d, J=7.5 Hz)

EXAMPLE 31

The following compounds were obtained according to a similar manner tothat of Example 30.

(1) 4-Nitrobenzyl7-[2-(4-chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480cm⁻¹

(2) 4-Nitrobenzyl7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 cm⁻¹

(3) 4-Nitrobenzyl7-[2-(3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 136° to 140° C. (dec.).

I.R. (Nujol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520,1450, 1325, 1280, 1160, 1125, 975, 850, 740 cm⁻¹

(4) 4-Nitrobenzyl7-[2-(4-fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1625, 1605, 1500, 1495 cm⁻¹

(5) 4-Nitrobenzyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetamido]-3-chloro-3-cephem-4-carboxylate(syn isomer), mp 91° to 100° C. (dec.).

N.M.R. (d₆ -DMSO+D₂ O, δ): 1.38 (9H, s), 1.80 (2H,m), 3.06 (2H, m),3.7-4.3 (4H, m), 5.33 (1H, d, J=5 Hz), 5.49 (2H, s), 5.95 (1H, d, J=5Hz), 7.74 (2H, d, J=9 Hz), 8.92 (2H, d, J=9 Hz)

(6) 4-Nitrobenzyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 cm⁻¹

EXAMPLE 32

A mixture of 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.37 g) and phosphorus oxychloride (3.67 g) inmethylane chloride (30 ml) was stirred for 2 hours at ambienttemperature and then cooled to -12° to -15° C. To the cold mixture wasadded dimethylformamide (2.4 ml) and the mixture was stirred for 45minutes at -8° to -10° C. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.9 g) and trimethylsilylacetamide (8 g) in methylene chloride (40 ml)was warmed to make a solution. The solution was cooled to -25° C. andadded to the above activated mixture. The reaction mixture was stirredfor 30 minutes at -8° to -10° C. and poured into a cold aqueous solutionof sodium bicarbonate. The mixture was stirred for 30 minutes at ambienttemperature and the aqueous layer was separated out. The aqueoussolution was adjusted to pH 1 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was dried over magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive a crude7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.1 g). The crude product was dissolved in an aqueoussolution of sodium bicarbonate and reprecipitated with an addition of10% hydrochloric acid to give pure object compound (1.15 g). mp 138° to140° C. (dec.)

I.R. (Nujol): 3350, 3230, 1780, 1680, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad s), 4.27 and 4.52 (2H, ABq, J=14Hz), 4.5-4.8 (2H, m), 5.10 (1H, d, J=5 Hz), 5.0-5.5 (2H, m), 5.78 (1H,dd, J=5 and 9 Hz), 5.7-6.3 (1H, m), 8.09 (2H, broad s), 9.48 (1H, s),9.53 (1H, d, J=9 Hz)

EXAMPLE 33

A mixture of2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (1.62 g) and phosphorus oxychloride (3.67 g) inmethylene chloride (30 ml) was stirred for 1.5 hours at ambienttemperature and then cooled to -12° to -15° C. To the cold mixture wasadded dimethylformamide (2.4 ml) and the mixture was stirred for 45minutes at -8° to -10° C. On the other hand, a mixture of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.9 g) and trimethylsilylacetamide (8 g) in methylene chloride (40 ml)was warmed to make a solution. The solution was cooled to -25° C. andadded to the above activated mixture. The reaction mixture was stirredfor 30 minutes at -10° C. and poured into a cold aqueous solution ofsodium bicarbonate. The mixture was stirred for 30 minutes at ambienttemperature and the aqueous layer was separated out. The aqueoussolution was adjusted to pH 2 with 10% hydrochloric acid and extractedwith ethyl acetate. The extract was dried over magnesium sulfate andevaporated to dryness. The residue was triturated with diethyl ether togive a crude7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.45 g). The crude product was dissolved in anaqueous solution of sodium bicarbonate and reprecipitated with anaddition of 10% hydrochloric acid to give pure object compound (1.42 g).mp 153° to 158° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.33 and 4.58 (2H, ABq, J=13Hz), 4.70 and 4.92 (2H, ABq, J=9 Hz), 5.17 (1H, d, J=5 Hz), 5.82 (1H,dd, J=5 and 8 Hz), 8.18 (2H, broad s), 9.55 (1H, s), 9.70 (1H, d, J=8Hz)

EXAMPLE 34

A mixture of dimethylformamide (6 ml) and phosphorus oxychloride (918mg) was stirred for 30 minutes at ambient temperature. Methylenechloride (6 ml) was added thereto and then2-dichloroacetoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer) (1.6 g) was added thereto at -20° to -25° C. The mixturewas stirred for 30 minutes at -10° to -15° C. To the resulting mixturewas added at -10° to -15° C. a solution of7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.0 g) and trimethylsilylacetamide (6 g) in methylene chloride (30 ml),and the mixture was stirred for 30 minutes at -5° to -15° C. Methylenechloride was evaporated from the reaction mixture and to the residuewere added ice-water and ethyl acetate. The resulting mixture containing7-[2-dichloroacetoxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was adjusted to pH 5 with an aqueous solution ofsodium bicarbonate. An aqueous layer was separated and ethyl acetate wasadded thereto. The mixture was adjusted to pH 2 with 10% hydrochloricacid and an insoluble substance was filtered off. The filtrate wasextracted three times with ethyl acetate. The extracts were dried overmagnesium sulfate and evaporated. The residue was triturated withdiethyl ether and precipitates were collected by filtration and washedwith diethyl ether to give7-[2-hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.9 g). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3200, 1780, 1680, 1620 cm⁻¹ N.M.R. (d₆ -DMSO, δ): 3.67(2H, broad s), 4.27 and 4.73 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz),5.83 (1H, dd, J=4 and 8 Hz), 8.80 (1H, s), 9.50 (1H, d, J=8 Hz), 9.53(1H, s), 12.22 (1H, s)

EXAMPLE 35

The following compounds were obtained according to similar manners tothose of Examples 32 to 34.

(1)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 140° to 145° C. (dec.)

I.R. (Nujol): 3330, 3250, 1780, 1680, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.47 (1H, t, J=2 Hz), 3.67 (2H, broad s), 4.28 and4.53 (2H, ABq, J=13 Hz), 4.77 (2H, d, J=2 Hz), 5.12 (1H, d, J=5 Hz),5.78 (1H, dd, J=5 and 8 Hz), 8.13 (2H, broad s), 9.55 (1H, s), 9.67 (1H,d, J=8 Hz)

(2)7-[2-Benzyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 135° C. (dec.)

I.R. (Nujol): 3360, 3250, 1780, 1680, 1625, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.63 (2H, broad s), 4.35 and 4.58 (2H, ABq, J=13Hz), 5.13 (1H, d, J=5 Hz), 5.23 (2H, s), 5.80 (1H, dd, J=5 and 8 Hz),7.38 (5H, s), 8.13 (2H, broad s), 9.57 (1H, s) 9.63 (1H, d, J=8 Hz)

(3)7-[2-(2-Phenoxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 163° to 167° C. (dec.).

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1600, 1530, 1500 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.30 and 3.60 (2H, ABq, J=18 Hz), 4.0-4.70 (6H,m), 5.10 (1H, d, J=4 Hz), 5.93 (1H, dd, J=4 and 8 Hz), 6.7-7.5 (5H, m),8.13 (2H, s), 9.50 (1H, s), 9.57 (1H, d, J=8 Hz)

(4)7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 168° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.17 (3H, s), 3.65 (2H, broad s), 4.30 and 4.57(2H, ABq, J=14 Hz), 5.12 (1H, d, J=4 Hz), 5.20 (2H, s), 5.80 (1H, dd,J=4 and 8 Hz), 8.17 (2H, s), 9.53 (1H, s), 9.62 (1H, d, J=8 Hz)

(5)7-[2-(2-Methylthioethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 125° to 130° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.08 (3H, s), 2.72 (2H, t, J=7 Hz), 3.68 (2H,broad s), 4.28 (2H, t, J=7 Hz), 4.30 and 4.55 (2H, ABq, J=13 Hz), 5.13(1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and 8 Hz), 8.15 (2H, broad s), 9.52(1H, d, J=8 Hz), 9.53 (1H, s)

(6)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 145° to 150° C. (dec.)

I.R. (Nujol): 3350, 3230, 1780, 1680, 1620, 1590, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.30 and 4.60 (2H, ABq, J=14Hz), 5.23 (1H, d, J=5 Hz), 5.92 (1H, dd, J=5 and 8 Hz), 7.0-7.6 (5H, m),8.30 (2H, broad s), 9.52 (1H, s), 9.83 (1H, d, J=8 Hz)

(7)7-[2-Cyanomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 105° to 110° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.6 and 3.76 (2H, ABq, J=18 Hz), 4.3 and 4.56 (2H,ABq, J=13 Hz), 5.12 (2H, s), 5.14 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and8 Hz), 8.20 (2H, broad s), 9.52 (1H, s), 9.78 (1H, d, J=8 Hz)

(8)7-[2-(N,N-Diethylcarbamoyl)methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3480, 3310, 3200, 1775, 1740, 1680, 1630, 1610, 1515 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.00 (3H, t, J=7 Hz), 1.08 (3H, t, J=7 Hz), 3.27(4H, q, J=7 Hz), 3.62 and 3.72 (2H, ABq, J=18 Hz), 4.53 and 4.55 (2H,ABq, J=14 Hz), 4.88 (2H, s), 5.15 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and9 Hz), 8.13 (2H, broad s), 9.55 (1H, s), 9.62 (1H, d, J=9 Hz)

(9)7-[2-(1-Ethoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 135° C. (dec.)

I.R. (Nujol): 3360, 3240, 1780, 1730, 1690, 1630, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.18 (3H, t, J=7 Hz), 1.50 (6H, s), 3.72 (2H,broad s), 4.13 (2H, q, J=7 Hz), 4.33 and 4.58 (2H, ABq, J=13 Hz), 5.18(1H, d, J=5 Hz), 5.85 (1H, dd, J=5 and 8 Hz), 8.18 (2H, broad s), 9.48(1H, d, J=8 Hz), 9.57 (1H, s)

(10)7-[2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 120° to 125° C. (dec.)

I.R. (Nujol): 3370, 3250, 1780, 1690, 1625, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 1.23 (3H, t, J=7 Hz), 3.72 (2H, broad s), 4.20(2H, q, J=7 Hz), 4.35 and 4.58 (2H, ABq, J=13 Hz), 4.78 (2H, s), 5.17(1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz), 8.20 (2H, broad s), 9.58(1H, d, J=8 Hz), 9.60 (1H, s)

(11)7-[2-Hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3200, 1780, 1680, 1620 cm⁻¹

(12)7-[2-{2-(2-Hexyloxyethoxy)ethoxyimino}2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 100° to 105° C. (dec.)

I.R. (Nujol): 3340, 3210, 1785, 1685, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 0.87 (3H, t, J=5 Hz), 0.87-1.73 (8H, m), 3.10-3.93(10H, m), 4.10-4.47 (2H, m), 4.30 and 4.58 (2H, ABq, J=13 Hz), 5.17 (1H,d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz), 8.12 (2H, broad s), 9.55 (1H,d, J=8 Hz), 9.57 (1H, s)

(13)7-[2-Mesylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 164° to 167° C. (dec.)

I.R. (Nujol): 3360, 3230, 1780, 1690, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.02 (3H, s), 3.72 (2H, broad s), 4.33 and 4.57(2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz), 5.30 (2H, s), 5.83 (1H, dd,J=5 and 8 Hz), 8.20 (2H, broad s), 9.55 (1H, s), 9.78 (1H, d, J=8 Hz)

(14)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 163° to 167° C. (dec.)

I.R. (Nujol): 3480, 3350, 3250, 1785, 1690, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.64 and 3.72 (2H, ABq, J=18 Hz), 3.90 (3H, s),4.24 and 4.38 (2H, ABq, J=14 Hz), 5.18 (1H, d, J=4 Hz), 5.98 (1H, dd,J=4 and 8 Hz), 7.30 (15H, s), 8.08 (2H, s), 9.84 (1H, d, J=8 Hz)

(15)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.)

I.R. (Nujol): 3450, 3350, 3200, 1790, 1690, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.73 (2H, broad s), 4.33 and 4.63 (2H, ABq, J=13Hz), 5.10 (1H, d, J=4 Hz), 6.03 (1H, dd, J=4 and 8 Hz), 7.37 (15H, s),8.13 (2H, s), 9.60 (1H, s), 9.87 (1H, d, J=8 Hz)

(16)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer). mp 131° to 133° C. (dec.)

I.R. (Nujol): 3350, 3240, 1780, 1730, 1680, 1530, 1240 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 2.07 (3H, s), 3.57 (2H, broad s), 4.5-5.1 (2H, m),4.7 (2H, broad s), 5.1-5.6 (2H, m), 5.15 (1H, d, J=4 Hz), 5.6-6.4 (1H,m), 5.84 (1H, dd, J=4.5 and 9 Hz), 8.13 (2H, broad s), 9.67 (1H, d, J=9Hz)

(17)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 154° to 156° C. (dec.)

I.R. (Nujol): 3380, 3245, 1780, 1680, 1625, 1527 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.53 and 3.77 (2H, ABq, J=14 Hz), 3.90 (3H, s),4.27 (2H, broad s), 4.5-4.8 (2H, m), 5.0-5.6 (2H, m), 5.15 (1H, d, J=4.5Hz), 5.6-6.3 (1H, m), 5.85 (1H, dd, J=4.5 and 9 Hz), 7.23 (2H, broad s),9.77 (1H, d, J=9 Hz)

(18)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3200, 1785, 1690, 1620, 1515 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.33 and 4.60 (2H, ABq, J=13Hz), 5.10 (1H, d, J=4 Hz), 5.73 (1H, dd, J=4 and 8 Hz), 7.33 (15H, s),8.17 (1H, d, J=8 Hz), 8.23 (2H, s), 9.60 (1H, s)

(19)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 161° to 164° C. (dec.)

I.R. (Nujol): 3350, 3220, 1770, 1670, 1620, 1525 cm⁻¹

(20)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). powder.

(21)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 169° C. (dec.)

I.R. (Nujol): 3350, 3200, 1768, 1670, 1610, 1522 cm⁻¹

(22)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

(23)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3480, 3350, 1770, 1690, 1620, 1530 cm⁻¹

(24)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm⁻¹

EXAMPLE 36

The following compounds were obtained according to similar manners tothose of Examples 14 to 17.

(1)7-[2-Hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3200,1780,1680,1620 cm⁻¹

(2)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 138° to 140° C. (dec.)

I.R. (Nujol): 3350,3230,1780,1680,1620,1530 cm⁻¹

(3)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 153° to 158° C.

I.R. (Nujol): 3350, 3250,1780,1680,1625 cm⁻¹

(4)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 140° to 145° C. (dec.)

I.R. (Nujol): 3330, 3250, 1780, 1680, 1620, 1530 cm⁻¹

(5)7-[2-Benzyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 135° C. (dec.)

I.R. (Nujol): 3360, 3250, 1780, 1680, 1625, 1530 cm⁻¹

(6)7-[2-(2-Phenoxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 163° to 167° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1630, 1600, 1530, 1500 cm⁻¹

(7)7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 168° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

(8)7-[2-(2-Methylthioethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 125° to 130° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1625, 1530 cm⁻¹

(9)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 145° to 150° C. (dec.)

I.R. (Nujol): 3350, 3230, 1780, 1680, 1620, 1590, 1530 cm⁻¹

(10)7-[2-Cyanomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 105° to 110° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

(11)7-[2-(N,N-Diethylcarbamoyl)methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.)

I.R. (Nujol): 3480, 3310, 3200, 1775, 1740, 1680, 1630, 1610, 1515 cm⁻¹

(12)7-[2-(1-Ethoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 130° to 135° C. (dec.)

I.R. (Nujol): 3360, 3240, 1780, 1730, 1690, 1630, 1530 cm⁻¹

(13)7-[2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 120° to 125° C. (dec.)

I.R. (Nujol): 3370, 3250, 1780, 1690, 1625, 1530 cm⁻¹

(14)7-[2-{2-(2-Hexyloxyethoxy)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 100° to 105° C. (dec.)

I.R. (Nujol): 3340, 3210, 1785, 1685, 1620, 1525 cm⁻¹

(15)7-[2-Mesylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 164° to 167° C. (dec.)

I.R. (Nujol): 3360, 3230, 1780, 1690, 1620, 1530 cm⁻¹

(16)7-[2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 163° to 167° C. (dec.)

I.R. (Nujol): 3480, 3350, 3250, 1785, 1690, 1620, 1530 cm⁻¹

(17)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 178° C. (dec.)

I.R. (Nujol): 3450, 3350, 3200, 1790, 1690, 1620, 1530 cm⁻¹

(18)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 154° to 156° C. (dec.)

I.R. (Nujol): 3380, 3245, 1780, 1680, 1625, 1527 cm⁻¹

(19)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3200, 1785, 1690, 1620, 1515 cm⁻¹

(20)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 161° to 164° C. (dec.)

I.R. (Nujol): 3350, 3220, 1770, 1670, 1620, 1525 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 3.6 (2H, broad s), 4.35 and 4.58 (2H, ABq,J=15 Hz), 4.2-4.8 (4H, m), 5.0-5.5 (2H, m), 5.05 (1H, d, J=5 Hz), 5.75(1H, d, J=5 Hz), 5.7-6.4 (1H, m)

(21)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). powder.

(22)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 169° C. (dec.)

I.R. (Nujol): 3350,3200,1768,1670,1610,1522 cm⁻¹

(23)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350,3250,1780,1680,1620,1530 cm⁻¹

(24)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 170° C. to 175° C. (dec.)

I.R. (Nujol): 3480,3350,1770,1690,1620,1530 cm⁻¹

(25)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350,3250,1780,1680,1620,1520 cm⁻¹

EXAMPLE 37

The following compounds were obtained according to similar manners tothose of Examples 22 to 25.

(1)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 161° to 164° C. (dec.)

I.R. (Nujol): 3350, 3220, 1770, 1670, 1620, 1525 cm⁻¹

(2)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 169° C. (dec.)

I.R. (Nujol): 3350, 3200, 1768, 1670, 1610, 1522 cm⁻¹

N.M.R. (d₆ -DMSO+D₂ O, δ): 3.41 (2H, broad s), 3.60 (2H, broad s),4.3-5.0 (4H, m), 5.05 (1H, d, J=4.5 Hz), 5.73 (1H, d, J=4.5 Hz), 4.9-5.6(2H, m), 5.7-6.4 (1H, m)

EXAMPLE 38

A mixture of7-[2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.95 g), conc.hydrochloric acid (0.6 ml) and methanol(10 ml) was stirred for 7 hours at ambient temperature. Methanol wasdistilled off from the reaction mixture and the residue was adjusted topH 5 by adding ethyl acetate and an aqueous solution of sodiumbicarbonate. To the separated aqueous layer was added ethyl acetate andthe mixture was adjusted to pH 2 with 10% hydrochloric acid. Theseparated ethyl acetate layer was dried over magnesium sulfate andevaporated in vacuo to a volume of 10 ml. Precipitates were collected byfiltration, washed with ethyl acetate and diethyl ether and dried togive7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.3 g). mp 170° to 175° C. (dec.)

I.R. (Nujol): 3480, 3350, 1770, 1690, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.61 and 3.73 (2H, ABq, J=18 Hz), 4.30 and 4.57(2H, ABq, J=13 Hz), 5.13 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz),8.03 (2H, s), 9.40 (1H, d, J=8 Hz), 9.57 (1H, s), 11.93 (1H, s)

EXAMPLE 39

The following compounds were obtained according to a similar manner tothat of Example 38.

(1)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer). mp 165° to 170° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1530 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 3.97 (3H, s), 4.33 (2H, broads), 5.13 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.03 (2H, s),9.43 (1H, d, J=8 Hz), 11.93 (1H, s)

(2)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer). mp 155° to 160° C. (dec.)

I.R. (Nujol): 3350, 3250, 1780, 1680, 1620, 1520 cm⁻¹

N.M.R. (d₆ -DMSO, δ): 3.70 (2H, broad s), 4.35 and 4.53 (2H, ABq, J=13Hz), 5.13 (1H, d, J=4 Hz), 5.73 (1H, dd, J=4 and 8 Hz), 8.03 (2H, s),8.92 (1H, d, J=8 Hz), 9.53 (1H, s)

EXAMPLE 40

A mixture of phosphorus pentachloride (1.89 g) and methylene chloride(20 ml) was stirred for 15 minutes at ambient temperature.2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.2 g) was added thereto at -15° C. and the mixturewas stirred for 30 minutes at -10° to -15° C. A solution of7-amino-3-cephem-4-carboxylic acid (1.4 g) and trimethylsilylacetamide(8.4 g) in methylene chloride (20 ml) was added thereto at -20° C. andthe mixture was stirred for 30 minutes at -10° to -15° C. and for 30minutes at 0° to 5° C. Methylene chloride was distilled off from thereaction mixture and to the residue were added ethyl acetate and a smallamount of water. The resulting solution was poured into an aqueoussolution of sodium bicarbonate and the aqueous layer was separated. Tothe aqueous layer was added ethyl acetate, and the mixture was acidifiedwith 6 N hydrochloric acid and then twice extracted with ethyl acetate.The extract was washed with water, dried over magnesium sulfate, treatedwith an activated charcoal and concentrated. The residue was trituratedwith diisopropyl ether and precipitates were collected by filtration togive pale yellow powder of7-[2-(1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (2.5 g), which is decomposed by 250° C.

IR (Nujol): 3400, 3250, 3150, 1770, 1720, 1680, 1610, 1520, 1290, 1240,1150, 980, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.50 (12H, broad s), 3.63 (2H, m), 4.73 (1H, q, J=7Hz), 5.17 (1H, d, J=5 Hz), 5.92 (1H, dd, J=5 and 8 Hz), 6.53 (1H, m),8.17 (2H, m), 9.4 and 9.6 (1H, d, J=8 Hz)

EXAMPLE 41

The following compounds were obtained according to similar manners tothose of Examples 1 to 3, 5, 7 to 12, 32 to 34 and 40.

(1)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 125° C. (dec.).

IR (Nujol): 3290, 3180, 1770, 1680, 1615, 1580, 1520, 1480 cm⁻¹

NMR (DMSO-d₆, δ): 3.73 (2H, broad s), 4.40 (2H, broad s), 5.17 (1H, d,J=5 Hz), 4.87-5.20 (2H, m), 5.20-5.60 (2H, m), 5.90 (1H, dd, J=5 and 8Hz), 5.60-6.30 (1H, m), 7.32 (2H, d, J=9 Hz), 7.48 (2H, d, J=9 Hz), 8.32(2H, broad s), 9.90 (1H, d, J=8 Hz)

(2)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

IR (Nujol): 3400, 3300, 3280, 1770, 1670, 1615, 1580, 1520, 1480 cm⁻¹

NMR (DMSO-d₆, δ): 3.72 (2H, broad s), 3.92 (3H, s), 4.32 (2H, broad s),5.18 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.25 (2H, d, J=9 Hz),7.42 (2H, d, J=9 Hz), 8.25 (2H, broad s), 9.85 (1H, d, J=8 Hz)

(3)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 120° to 125° C. (dec.).

IR (Nujol): 3400, 3300, 3190, 1770, 1720, 1650, 1620, 1580, 1520, 1480cm⁻¹

NMR (DMSO-d₆, δ): 2.02 (3H, s), 3.58 (2H, broad s), 4.75 and 4.98 (2H,ABq, J=13 Hz), 5.22 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.27(2H, d, J=9 Hz), 7.42 (2H, d, J=9 Hz), 8.28 (2H, broad s), 9.85 (1H, d,J=8 Hz)

(4)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

IR (Nujol): 3400, 3270, 3190, 1770, 1680, 1620, 1585, 1520, 1480 cm⁻¹

NMR (DMSO-d₆, δ): 2.70-3.10 (2H, m), 3.70 (2H, broad s), 4.10-4.60 (4H,m), 5.20 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.28 (2H, d, J=9Hz), 7.45 (2H, d, J=9 Hz), 8.30 (2H, broad s), 9.85 (1H, d, J=8 Hz)

(5)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3400, 3300, 3190, 1765, 1700, 1620, 1580, 1540, 1520, 1480cm⁻¹

NMR (DMSO-d₆, δ): 3.80 (2H, broad s), 4.28 (2H, broad s), 4.73 (2H, s),5.27 (1H, d, J=5 Hz), 5.90 (1H, dd, J=5 and 8 Hz), 7.12 (1H, d, J=10Hz), 7.32 (2H, d, J=9 Hz), 7.47 (2H, d, J=9 Hz), 7.72 (1H, d, J=10 Hz),8.30 (2H, broad s), 9.92 (1H, d, J=8 Hz)

(6)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo-[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3350, 3240, 1780, 1685, 1625, 1530, 1490 cm⁻¹

NMR (DMSO-d₆, δ): 3.70 (2H, broad s), 4.22 and 4.62 (2H, ABq, J=13 Hz),5.22 (1H, d, J=5 Hz), 5.93 (1H, dd, J=5 and 8 Hz), 7.27 (2H, d, J=9 Hz),7.42 (2H, d, J=9 Hz), 7.73 (1H, d, J=9 Hz), 8.28 (2H, broad s), 8.59(1H, d, J=9 Hz), 9.87 (1H, d, J=8 Hz)

(7)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° to 110° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1780, 1720, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 3.50-3.83 (2H, m), 4.37 and 4.60 (2H,ABq, J=13 Hz), 5.10 and 5.18 (1H, d, J=5 Hz), 5.63 (1H, s), 5.67-6.0(1H, m), 7.47 (5H, s), 8.20 (2H, broad s), 9.62 (1/2H, s), 9.64 (1/2H,s), 9.47-9.77 (1H, m)

(8)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 90° to 95° C. (dec.).

IR (Nujol): 3400, 3380, 3230, 1780, 1730, 1685, 1635, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.38 (9H, s), 3.60 (2H, broad s), 5.0-5.20 (1H, m),5.63 (1H, s), 5.72-6.03 (1H, m), 6.37-6.67 (1H, m), 7.47 (5H, s), 8.18(2H, broad s), 9.43-9.70 (1H, m)

(9)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° to 110° C. (dec.).

IR (Nujol): 3360, 3220, 1785, 1690, 1625, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.38 (18H, s), 3.17-3.87 (4H, m), 4.17-4.65 (4H, m),5.0-5.28 (1H, m), 5.12 (1H, s), 5.58-6.0 (1H, m), 7.47 (5H, s), 8.17(2H, broad s), 9.45-9.75 (1H, m)

(10)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

IR (Nujol): 3400, 3260, 3190, 2580, 1765, 1710, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.92 (2H, t, J=6 Hz), 3.47 (1H, t, J=2 Hz), 3.67 (2H,broad s), 4.17-4.60 (4H, m), 4.77 (2H, d, J=2 Hz), 5.08 (1H, d, J=5 Hz),5.77 (1H, dd, J=5 and 8 Hz), 8.08 (2H, broad s), 9.57 (1H, d, J=8 Hz)

(11)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer).

IR (Nujol): 3400, 3270, 3180, 1770, 1720, 1655, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.98 (3H, s), 2.45 (1H, t, J=2 Hz), 3.48 (2H, broads), 4.72 (2H, d, J=2 Hz), 4.67 and 4.92 (2H, ABq, J=13 Hz), 5.08 (1H, d,J=5 Hz), 5.77 (1H, dd, J=5 and 8 Hz), 8.07 (2H, broad s), 9.55 (1H, d,J=8 Hz)

(12)7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3350, 3250, 3180, 1790, 1720, 1660, 1630, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 3.57 (2H, broad s), 4.60 (2H, s), 5.07(1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 6.47 (1H, broad s), 8.13(2H, s), 9.50 (1H, d, J=8 Hz)

(13)7-[2-(Thiolan-1,1-dioxide-3-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.30-2.50 (2H, m), 3.0-3.57 (4H, m), 3.70 (2H, broads), 4.33 and 4.57 (2H, ABq, J=13 Hz), 5.0-5.15 (1H, m), 5.17 (1H, d, J=4Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.23 (2H, s), 9.60 (1H, s), 9.67 (1H,d, J=8 Hz)

(14)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.63 (2H, broad s), 4.23 and 4.43 (2H, ABq, J=14 Hz),4.60-4.73 (2H, m), 5.10 (1H, d, J=4 Hz), 5.30 (2H, s), 5.07-5.50 (2H,m), 5.67-6.20 (2H, m), 8.15 (2H, s), 9.63 (1H, d, J=8 Hz)

(15)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

IR (Nujol): 3250, 3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.47 (1H, t, J=2 Hz), 3.63 (2H, broad s), 4.22 and4.43 (2H, ABq, J=14 Hz), 5.07 (1H, d, J=4 Hz), 5.28 (2H, s), 5.80 (1H,dd, J=4 and 8 Hz), 8.15 (2H, s), 9.63 (1H, d, J=8 Hz)

(16)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.87 (2H, t, J=6 Hz), 3.63 (2H, broad s), 4.37 (2H, t,J=6 Hz), 4.20 and 4.47 (2H, ABq, J=14 Hz), 4.57-4.67 (2H, m), 5.07 (1H,d, J=4 Hz), 5.10-5.43 (2H, m), 5.67-6.13 (2H, m), 8.10 (2H, s), 9.58(1H, d, J=8 Hz)

(17)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1700, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.50 (9H, s), 3.00 (2H, t, J=6 Hz), 3.73 (2H, broads), 4.43 (2H, broad s), 4.50 (2H, t, J=6 Hz), 4.67 (2H, s), 5.17 (1H, d,J=4 Hz), 5.87 (1H, dd, J=4 and 8 Hz), 8.18 (2H, s), 9.53 (1H, d, J=8 Hz)

(18)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 220° to 225° C. (dec.).

IR (Nujol): 3300, 1700, 1680, 1605, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 1.96-2.10 (2H, m), 2.38-2.50 (4H, m),2.60 (3H, s), 2.95-3.10 (6H, m), 3.52 and 3.65 (2H, ABq, J=16 Hz),4.20-4.40 (4H, m), 4.60 (2H, s), 5.06 (1H, d, J=4 Hz), 5.70 (1H, dd, J=4and 8 Hz), 8.12 (2H, s), 9.44 (1H, d, J=8 Hz),

(19)7-[2-(1-t-Butoxycarbonyl-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 130° to 140° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1780, 1720-1680, 1620, 1520, 1460, 1370,1230, 1150, 1030, 730 cm⁻¹

NMR (DMSO-d₆, δ): 1.03 (6H, d, J=7 Hz), 1.43 (9H, s), 2.03 (3H, s),1.9-2.2 (1H, m), 3.6 (2H, m), 4.26 and 4.34 (1H, d, J=6 Hz), 4.68 and5.05 (2H, ABq, J=13 Hz), 5.19 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8Hz), 8.10 (2H, broad s), 9.48 (1H, d, J=8 Hz)

(20)7-[2-(1-t-Butoxycarbonylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 101° to 105° C. (dec.).

IR (Nujol): 3300, 3150, 1770, 1720, 1620, 1520, 1450, 1370, 1250, 1150,1010, 900, 840, 720 cm⁻¹

NMR (DMSO-d₆, δ): 0.93 (3H, t, J=7 Hz), 1.42 (9H, s), 1.8 (2H, m), 3.7(2H, m), 4.6 (3H, m), 5.18 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz),8.20 (2H, broad s), 9.5 (1H, m), 9.58 (1H, s)

(21)7-[2-(1-t-Butoxycarbonylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosphoranicacid (syn isomer), mp 95° to 105° C. (dec.).

IR (Nujol): 3400,3300, 3200, 1780, 1720, 1620, 1530, 1230, 1150, 1010,890, 840, 740 cm⁻¹

NMR (DMSO-d₆, δ): 0.95 (3H, t, J=7 Hz), 1.39 (9H, s), 1.8 (2H, m), 2.02(3H, s), 3.5 (2H, m), 4.47 (1H, m), 4.67 and 5.03 (2H, ABq, J=13 Hz),5.14 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz), 8.07 (2H, broad s),9.37 and 9.43 (1H, d, J=8 Hz)

(22)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 128° C. (dec.).

IR (Nujol): 3280, 3180, 1770, 1720, 1680, 1620, 1520, 1240, 1150, 1000,740, 720 cm⁻¹

NMR (DMSO-d₆, δ): 1.4 (12H, m), 3.76 (2H, m), 4.30 and 4.67 (2H, ABq,J=13 Hz), 4.70 (1H, q, J=7 Hz), 5.22 (1H, d, J=5 Hz), 5.88 (1H, dd, J=5and 8 Hz), 8.20 (2H, broad s), 9.47 (1H, m), 9.60 (1H, s)

(23)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 138° to 145° C. (dec.).

IR (Nujol): 3280, 3180, 1780, 1720, 1680, 1620, 1520, 1230, 1150, 840cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (12H, m), 2.07 (3H, s), 3.58 (2H, m), 4.5-5.1(3H, m), 5.19 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 8.10 (2H,broad s), 9.40 and 9.50 (1H, d, J=8 Hz)

(24)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 115° to 120° C. (dec.).

IR (Nujol): 3280, 3170, 1780, 1720, 1680, 1520, 1140, 990, 750 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 1.46 (6H, s), 3.7 (2H, m), 4.26 and 4.63(2H, ABq, J=13 Hz), 5.18 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz),8.13 (2H, broad s), 9.40 (1H, d, J=8 Hz), 9.53 (1H, s)

(25)7-[2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 143° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1670, 1620, 1520, 1245, 1150, 1060,995, 840 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 1.8 (4H, m), 2.1 (4H, m), 3.7 (2H, m),4.27 and 4.68 (2H, ABq, J=13 Hz), 5.18 (1H, d, J=5 Hz), 5.85 (1H, dd,J=5 and 8 Hz), 8.1 (2H, broad s), 9.39 (1H, d, J=8 Hz), 9.53 (1H, s)

(26)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamino]cephalosporanicacid (syn isomer), mp 135° to 140° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1780, 1720, 1690, 1620, 1540, 1300, 1220,1140, 1030, 990, 840, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.57 (9H, s), 1.62 (6H, s), 2.03 (3H, s), 3.57 (2H,m), 4.69 and 5.06 (2H, ABq, J=13 Hz), 5.19 (1H, d, J=5 Hz), 5.89 (1H,dd, J=5 and 8 Hz), 8.21 (2H, broad s), 9.32 (1H, d, J=8 Hz)

(27)7-[2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 98° to 102° C. (dec.).

IR (Nujol): 3350, 3230, 1790, 1730, 1630, 1530, 1340, 1160, 1070, 1040,1000 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (9H, s), 1.80 (4H, m), 2.10 (4H, m), 2.13 (3H,s), 3.60 (2H, m), 4.73 and 5.1 (2H, ABq, J=14 Hz), 5.22 (1H, d, J=5 Hz),5.88 (1H, dd, J=5 and 8 Hz), 8.15 (2H, m), 9.43 (1H, d, J=8 Hz)

(28)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 96° to 100° C. (dec.).

IR (Nujol): 3300, 3150, 1780, 1680, 1570, 1240, 1160, 990 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (18H, s), 1.52 (6H, s), 3.33 (2H, m), 3.67 (2H,m), 4.30 (4H, m), 5.10 (1H, d, J=5 Hz), 5.85 (1H, dd, J=5 and 8 Hz),6.92 (1H, m), 8.13 (2H, m), 9.40 (1H, d, J=8 Hz)

(29)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 215° C.

IR (Nujol): 3400, 3300, 3150, 1780, 1710, 1690, 1620, 1520, 1240, 1140,980 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 1.47 (6H, s), 3.60 (2H, m), 5.17 (1H, d,J=5 Hz), 5.92 (1H, dd, J=5 and 8 Hz), 6.50 (1H, m), 8.22 (2H, m), 9.50(1H, d, J=8 Hz)

(30)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 96° to 100° C. (dec.).

IR (Nujol): 3300, 3150, 1780, 1720, 1680, 1620, 1520, 1240, 1150, 1090,1000 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (12H, broad s), 3.67 (2H, m), 4.2 and 4.50 (2H,ABq, J=13 Hz), 4.67 (1H, q, J=6 Hz), 4.93 (2H, m), 5.07 (1H, d, J=5 Hz),5.13-5.37 (2H, m), 5.83 (1H, dd, J=5 and 8 Hz), 5.83-6.22 (1H, m), 8.10(2H, broad s), 9.40 and 9.52 (1H, d, J=8 Hz)

(31)7-[2-(1-Phenylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 175° C.

IR (Nujol): 3400, 3250, 3150, 1750, 1650, 1610, 1520, 1400, 1240, 1160,1060, 1000, 700 cm⁻¹

NMR (DMSO-d₆, δ): 1.57 (3H, d, J=8 Hz), 3.73 (2H, m), 4.32 and 4.72 (2H,ABq, J=13 Hz), 5.22 (1H, d, J=5 Hz), 5.3-5.5 (1H, m), 5.93 (2H, dd, J=5and 8 Hz), 7.36 (5H, m), 8.13 (2H, m), 9.57 (1H, s), 9.72 (1H, d, J=8Hz)

(32)7-[2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 210° C.

IR (Nujol): 3450, 3300, 3200, 1760, 1660, 1560, 1290, 1210, 1000, 970,940, 730 cm⁻¹

NMR (DMSO-d₆, δ): 3.63 (2H, m), 5.17 (1H, d, J=5 Hz), 5.91 (1H, dd, J=5and 8 Hz), 6.41 (1H, m), 7.13-7.73 (3H, m), 8.28 (2H, broad s), 9.87(1H, d, J=8 Hz)

(33)7-[2-(p-Tolyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 150° C., which is a mixturewith o-tolyl isomer.

IR (Nujol): 3350, 3250, 1780, 1680, 1630, 1530, 1510, 1230, 1050, 910,820 cm⁻¹

NMR (DMSO-d₆, δ): 2.23 (1/5H, s), 2.27 (9/5H, s), 3.71 (2H, m), 4.21 and4.61 (2H, ABq, J=13 Hz), 5.23 (1H, d, J=5 Hz), 5.90 (1H, m), 7.16 (4H,m), 8.23 (2H, m), 9.56 (1H, s), 9.86 (1H, d, J=8 Hz)

(34)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 155° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060,980, 930, 700 cm⁻¹

NMR (DMSO-d₆, δ): 3.56 and 3.82 (2H, ABq, J=18 Hz), 4.20 and 4.60 (2H,ABq, J=14 Hz), 4.95 (2H, m), 5.18 (1H, d, J=5 Hz), 5.12-5.24 (2H, m),5.92 (1H, dd, J=5 and 8 Hz), 5.72-6.12 (1H, m), 7.50 (4H, m), 8.26 (2H,m), 9.84 (1H, d, J=8 Hz)

(35)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 170° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060,930, 790, 700 cm⁻¹

NMR (DMSO-d₆, δ): 3.77 (2H, m), 3.97 (3H, s), 4.37 (2H, m), 5.27 (1H, d,J=5 Hz), 5.95 (1H, dd, J=5 and 8 Hz), 7.60 (4H, m), 8.33 (2H, m), 9.97(1H, d, J=8 Hz)

(36)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 170° C.

IR (Nujol): 3450, 3350, 3200, 1780, 1710, 1680, 1610, 1510, 1590, 1240,1200, 1170, 1090, 990, 910, 840 cm⁻¹

NMR (DMSO-d₆, δ): 3.73 (2H, m), 3.93 (3H, s), 4.33 (2H, m), 5.23 (1H, d,J=5 Hz), 5.90 (1H, dd, J=5 and 8 Hz), 7.17-7.28 (4H, m), 8.37 (2H, m),9.87 (1H, d, J=8 Hz)

(37)7-[2-(2,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 240° C.

IR (Nujol): 3250, 1770, 1660, 1620, 1540, 1520, 1280, 1230, 1100, 1050,970, 920, 810, 750 cm⁻¹

NMR (DMSO-d₆, δ): 3.56 (2H, m), 5.11 (1H, d, J=5 Hz), 5.91 (1H, dd, J=5and 8 Hz), 6.47 (1H, m), 7.47-7.63 (3H, m), 8.21 (2H, m), 9.81 (1H, d,J=8 Hz)

(38)7-[2-(2,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 165° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1230, 1100, 1060,960, 910, 810 cm⁻¹

NMR (DMSO-d₆, δ): 3.71 (2H, m), 4.23 and 4.67 (2H, ABq, J=14 Hz), 5.25(1H, d, J=5 Hz), 5.93 (1H, dd, J=5 and 8 Hz), 7.50-7.67 (3H, m), 8.25(2H, m), 9.57 (1H, s), 9.88 (1H, d, J=8 Hz)

(39)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 218° C. (dec.).

IR (Nujol): 3350, 3250, 3140, 3050, 1750, 1705, 1665, 1625, 1550, 1535cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.6-2.6 (4H, m), 2.00 (3H, s), 3.0-3.9 (2H, m),5.05 (1H, d, J=4.5 Hz), 5.2-5.5 (1H, m), 5.70 (1H, d, J=4.5 Hz), 5.7-6.3(2H, m)

(40)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 212° C. (dec.).

IR (Nujol): 3350, 3120, 3050, 1750, 1705, 1668, 1625, 1556, 1534 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.3-2.2 (8H, m), 2.03 (3H, s), 3.0-3.9 (2H, m),4.77 (1H, broad s), 5.10 (1H, d, J=4.5 Hz), 5.73 (1H, d, J=4.5 Hz)

(41)7-[2-(2-Cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 205° C. (dec.).

IR (Nujol): 3340, 3250, 3120, 3050, 1750, 1705, 1665, 1625, 1535 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.3-2.4 (6H, m), 2.03 (3H, s), 3.1-3.7 (2H, m),4.70 (1H, broad s), 5.10 (1H, d, J=4.5 Hz), 5.73 (1H, d, J=4.5 Hz),5.7-6.0 (2H, m)

(42)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 142° to 148° C. (dec.).

IR (Nujol): 3300, 3200, 1775, 1650, 1630, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.41 (3H, d, J=7.5 Hz), 1.9-2.6 (4H, m), 3.5-4.1(1H, m), 5.16 (1H, d, J=4.5 Hz), 5.2-5.5 (1H, m), 5.6-6.4 (3H, m), 6.62(1H, d, J=6 Hz)

(43)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3200, 3160, 1773, 1685, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.41 (9H, s), 1.6-2.1 (2H, m), 2.8-3.3 (2H, m),3.75 (2H, broad s), 4.0-4.5 (2H, m), 4.35 and 4.65 (2H, ABq, J=14 Hz),5.20 (1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz), 9.58 (1H, s)

(44)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3200, 3160, 1775, 1720, 1700, 1675, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.37 (9H, s), 1.5-1.9 (2H, m), 2.6-3.2 (2H, m),3.4-3.9 (4H, m), 3.9-4.4 (6H, m), 5.10 (1H, d, J=5 Hz), 5.80 (1H, d, J=5Hz)

(45)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1775, 1710, 1700, 1670, 1650, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.40 (9H, s), 1.6-2.1 (2H, m), 2.71 (3H, s),2.9-3.3 (2H, m), 3.71 (2H, broad s), 4.0-4.8 (4H, m), 5.18 (1H, d, J=4.5Hz), 5.88 (1H, d, J=4.5 Hz)

(46)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 81° to 119° C. (dec.).

IR (Nujol): 3300, 3180, 1773, 1715, 1700, 1670, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.35 (9H, s), 1.5-2.0 (2H, m), 2.7-3.2 (2H, m),3.68 (2H, broad s), 3.9-4.5 (4H, m), 3.92 (3H, s), 5.12 (1H, d, J=4.5Hz), 5.83 (1H, d, J=4.5 Hz)

(47)7-[2-{4-(N-t-Butoxycarbonylaminomethyl)benzyloxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3170, 1760, 1680 cm⁻¹

NMR (DMSO-d₆, δ): 1.65 (9 H, s), 2.0 (3H, s), 3.4 (2H, m), 4.14 (2H, d,J=6 Hz), 5.1 (1H, d, J=4.5 Hz), 5.2 (2H, s), 5.73 (1H, dd, J=4.5 and 8Hz)

(48)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-hydroxycepham-4-carboxylicacid (syn isomer), mp 169° to 173° C. (dec.).

IR (Nujol): 3440, 3250, 1750, 1660, 1520, 1400, 1240, 1060, 990, 720cm⁻¹

NMR (DMSO-d₆, δ): 1.7 (8H, m), 2.77 (1H, m), 3.0-3.5 (1H, m), 3.7-4.1(1H, s), 4.43 (1H, d, J=6 Hz), 4.73 (1H, m), 5.16 (1H, d, J=5 Hz), 5.47(1H, dd, J=5 and 8 Hz), 8.02 (2H, broad s), 9.33 (1H, d, J=8 Hz)

(49)7-[2-{1-(Cyclohexyloxycarbonyl)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 163° C. (dec.).

IR (Nujol): 3420, 3300, 3180, 1775, 1720, 1685, 1610, 1520, 1290, 1230,1040, 980, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.50 (3H, d, J=6 Hz), 1.0-2.1 (10H, m), 3.62 (2H, m),4.80 (1H, q, J=6 Hz), 4.6-5.0 (1H, m), 5.15 (1H, d, J=5 Hz), 5.90 (1H,dd, J=5 and 8 Hz), 6.50 (1H, m), 8.13 (2H, broad s), 9.39 (1/2H, d, J=8Hz), 9.53 (1/2H, d, J=8 Hz)

(50)7-[2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 169° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1710, 1680, 1610, 1520, 1290, 1240,1150, 1000, 970, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.42 (9H, s), 1.77 (4H, m), 2.05 (4H, m), 3.60 (2H,m), 5.13 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 6.47 (1H, m),8.13 (2H, m), 9.33 (1H, d, J=8 Hz)

(51)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetaido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 173° C. (dec.).

IR (Nujol): 3400, 3280, 3150, 1760, 1665, 1610, 1520 cm⁻¹

(52)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N,N-dimethylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 3280, 3160, 1760, 1665, 1610, 1520 cm⁻¹

(53)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 85° to 90° C. (dec.).

IR (Nujol): 3400, 3290, 3200, 1770, 1680, 1620, 1520 cm⁻¹

(54)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

(55)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-(carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 132° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(56)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 192° to 195° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1680, 1520, 1450, 1360, 1240, 1160, 1620,1020, 730 cm⁻¹

(57)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 192° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1450, 1360, 1250, 1160,1000, 730-710 cm⁻¹

(58)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1775, 1715, 1675, 1650, 1615 cm⁻¹

(59)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 110° to 115° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 1000, 720 cm⁻¹

(60)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 205° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1520, 1250, 1160, 1000 cm⁻¹

(61)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-morpholinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 194° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1610, 1530, 1240, 1180, 1090, 1060,880, 760 cm⁻¹

(62)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1770, 1680, 1520, 1240, 1160, 990 cm⁻¹

(63)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 214° C. (dec.).

IR (Nujol): 3250, 3180, 1760, 1720-1660, 1590, 1520, 1240, 1090, 1050,720 cm⁻¹

(64)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{4-(N-t-butoxycarbonylamino)butyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1240, 1160, 1090, 1060,890 cm⁻¹

(65)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-piperidinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 223° to 228° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 cm⁻¹

(66)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 3200, 1765, 1720, 1660, 1620, 1520 cm⁻¹

(67)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{6-(N-t-butoxycarbonylamino)hexyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder.

(68)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 215° C. (dec.).

IR (Nujol): 3300, 1770, 1680, 1620, 1520, 1240, 1140 cm⁻¹

(69)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3450, 3300, 3210, 1770, 1670, 1620, 1525 cm⁻¹

(70)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1660, 1640, 1520 cm⁻¹

(71)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 189° C. (dec.).

IR (Nujol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230,1180, 1100, 1020, 900, 730 cm⁻¹

(72)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 188° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1530, 1380, 1280, 1230, 1180,1100, 1050, 1010, 730 cm⁻¹

(73)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720 cm⁻¹

(74)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(4-aminobutyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 191° to 194° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890,740, 720 cm⁻¹

(75)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 203° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1160, 990 cm⁻¹

(76)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 202° to 205° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730cm⁻¹

(77)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 207° to 210° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1170, 1090, 1060,1040, 990 cm⁻¹

(78)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(6-aminohexyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1670, 1620, 1520, 1240, 1180, 1060 cm⁻¹

(79)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 183° C. (dec.).

IR (Nujol): 3150, 1765, 1660, 1630, 1570, 1520 cm⁻¹

(80)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 185° C. (dec.).

IR (Nujol): 3140, 1760, 1660, 1610, 1580, 1520 cm⁻¹

(81)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 192° to 195° C. (dec.).

IR (Nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 cm⁻¹

(82)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 184° C. (dec.).

IR (Nujol): 3160, 1760, 1660, 1590 cm⁻¹

(83)7-[2-(4-Aminomethylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid formate (syn isomer), mp 230° to 240° C. (dec.).

IR (Nujol): 1750 cm⁻¹

(84)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 cm⁻¹

(85)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520 cm⁻¹

(86)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1520 cm⁻¹

(87)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 195° C. (dec.).

IR (Nujol): 3400, 3300, 3150, 1765, 1670, 1610, 1520 cm⁻¹

(88)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

IR (Nujol): 3350, 3250, 1770, 1720, 1680, 1630, 1530 cm⁻¹

(89)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm⁻¹

(90)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanicacid (syn isomer).

IR (Nujol): 3400-3150, 1770, 1730-1670, 1720, 1620, 1460, 1370, 1230,1030, 730 cm⁻¹

(91)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 153° to 158° C. (dec.).

IR (Nujol): 3300,3180, 1770, 1720-1670, 1620, 1520, 1220, 1060, 1000,900, 730 cm⁻¹

(92)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 115° to 120° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1720-1670, 1620, 1520, 1230,1030-1010, 890, 740-720 cm⁻¹

(93)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 168° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000,900, 720 cm⁻¹

(94)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 164° to 167° C. (dec.).

IR (Nujol): 3300, 3200, 2800-2300, 1770, 1720-1660, 1620, 1520, 1160,1060, 990, 800 cm⁻¹

(95)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 169° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1660, 1620, 1520, 1240, 1180, 1060,1000, 720 cm⁻¹

(96)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 215° to 220° C. (dec.).

IR (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000,980, 740 cm⁻¹

(97)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 180° C.

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1520, 1260, 1100, 1040, 1000cm⁻¹

(98)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 230° to 235° C. (dec.).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240,1170, 970, 740 cm⁻¹

(99)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 212° to 217° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000,970, 730 cm⁻¹

(100)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1710, 1670, 1520, 1230, 1040 cm⁻¹

(101)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, 1170, 990 cm⁻¹

(102)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3300, 1770, 1650, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.50-1.80 (8H, m), 1.80-2.10 (2H, m), 2.30-2.50 (4H,m), 2.60 (3H, s), 2.8-3.3 (6H, m), 3.60 (2H, broad s), 4.30-4.50 (4H,m), 4.67-4.83 (1H, m), 5.10 (1H, d, J=4 Hz), 5.77 (1H, dd, J=4 and 8Hz), 8.17 (2H, s), 9.50 (1H, d, J=8 Hz)

(103)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1770, 1710, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.40-2.0 (8H, m), 3.53 (2H, broad s), 4.67 and 4.85(2H, ABq, J=13 Hz), 4.67-5.07 (1H, m), 5.15 (1H, d, J=5 Hz), 5.78 (1H,dd, J=5 and 8 Hz), 6.55 (2H, broad s), 8.08 (2H, broad s), 9.45 (1H, d,J=8 Hz)

(104)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1770, 1710, 1670, 1615, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.97-2.47 (4H, m), 3.50 (2H, broad s), 4.65 and 4.85(2H, ABq, J=13 Hz), 5.12 (1H, d, J=5 Hz), 5.17-5.50 (1H, m), 5.67-6.27(3H, m), 6.55 (2H, broad s), 8.10 (2H, broad s), 9.47 (1H, d, J=8 Hz)

(105)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer),

IR (Nujol): 3420, 3400, 3270, 3180, 2430, 1790, 1775, 1690, 1675, 1640,1615, 1600, 1495 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (3H, d, J=7 Hz), 1.5-2.1 (8H, m), 3.73 (1H, q,J=7 Hz), 4.5-4.9 (1H, m), 5.07 (1H, d, J=5 Hz), 5.84 (1H, dd, J=5 and 9Hz), 6.50 (1H, d, J=6 Hz), 8.02 (2H, broad s), 9.38 (1H, d, J=9 Hz)

(106)7-[2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 2.27-2.70 (2H, m), 3.70 (2H, broad s), 4.17-4.73 (4H,m), 5.15 (1H, d, J=4 Hz), 5.18 (1H, t, J=7 Hz), 5.83 (1H, dd, J=4 and 8Hz), 8.13 (2H, broad s), 9.50 (1H, s), 9.60 (1H, d, J=8 Hz)

(107)7-[2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 2.35-2.67 (2H, m), 3.57 (2H, broad s), 4.17-4.50 (2H,m), 5.07 (1H, d, J=4 Hz), 5.15 (1H, t, J=8 Hz), 5.82 (1H, dd, J=4 and 8Hz), 6.43 (1H, t, J=5 Hz), 8.17 (2H, broad s), 9.60 (1H, d, J=8 Hz)

(108)7-[2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3400-3250, 1780, 1680, 1620, 1520, 1240, 1220, 1160, 1100,1000, 740, 720 cm⁻¹

NMR (DMSO-d₆, δ): 1.0-2.3 (15H, m), 1.40 (9H, s), 3.0 (2H, m), 3.7 (2H,m), 4.3 (4H, m), 4.5-5.0 (1H, m), 4.77 (1H, q, J=7 Hz), 5.13 (1H, d, J=5Hz), 5.86 (1H, m), 6.83 (1H, m), 8.12 (2H, broad s), 9.37 (1/2H, d, J=8Hz), 9.51 (1/2H, d, J=8 Hz)

(109)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 177° to 180° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1730, 1680, 1610, 1520, 1240, 1160,1040, 980, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (3H, d, J=7 Hz), 3.57 (2H, m), 4.88 (1H, q, J=7Hz), 5.10 (1H, d, J=5 Hz), 5.18 (2H, s), 5.87 (1H, dd, J=5 and 8 Hz),6.45 (1H, m), 7.31 (5H, broad s), 8.10 (2H, broad s), 9.40 and 9.55 (1H,d, J=8 Hz)

(110)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 113° to 117° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1520, 1250, 1160, 1100, 1040,1000, 740, 700 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (9H, s), 1.53 (3H, d, J=6 Hz), 2.0 (2H, m), 3.03(2H, m), 3.70 (2H, m), 4.10-4.67 (4H, m), 4.88 (1H, q, J=6 Hz), 5.10(1H, d, J=5 Hz), 5.17 (2H, s), 5.80 (1H, dd, J=5 and 8 Hz), 6.53 (1H,m), 7.30 (5H, s), 8.10 (2H, broad s), 9.40 and 9.55 (1H, d, J=8 Hz)

(111)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 147° to 151° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1610, 1520, 1280, 1235,1155, 1045, 980, 740 cm⁻¹

NMR (DMSO-d₆, δ): 0.87 (3H, t, J=6 Hz), 1.46 (3H, d, J=7 Hz), 0.8-1.8(4H, m), 3.6 (2H, m), 4.08 (2H, t, J=6 Hz), 4.74 (1H, q, J=7 Hz), 5.08(1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8 Hz), 6.4 (1H, m), 8.07 (2H,broad s), 9.39 and 9.44 (1H, d, J=6 Hz)

(112)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 155° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1700, 1620, 1520, 1250, 1160, 1100, 1040,1000, 740, 720 cm⁻¹

NMR (DMSO-d₆, δ): 0.26 (3H, t, J=7 Hz),1.40(9H,s), 1.0-1.7 (4H, m), 1.43(3H, d, J=7 Hz), 1.7-2.3 (2H, m), 3.0 (2H, m), 3.7 (2H, m), 4.0-4.5 (6H,m), 4.77 (1H, q, J=7 Hz), 5.15 (1H, d, J=6 Hz), 5.8 (1H, m), 6.9 (1H,m), 8.13 (2H, broad s), 9.5 (1H, m)

(113)7-[2-(2-D-Phenylglycylaminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 204° to 222° C. (dec.).

IR (Nujol): 3260, 3150, 1760, 1665, 1616, 1512, 1400, 1045 cm⁻¹

(114)7-[2-(3-D-Phenylglycylaminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 203° to 231° C. (dec.).

IR (Nujol): 3280, 1170, 1760, 1660, 1600, 1520, 1400 cm⁻¹

NMR (D₂ O+DCl, δ): 1.47 (3H, d, J=7.5 Hz), 1.7-2.3 (2H, m), 3.40 (2H, t,J=7 Hz), 3.88 (1H, q, J=7.5 Hz), 4.33 (2H, t, J=6 Hz), 5.18 (1H, d,J=4.5 Hz), 5.20 (1H, s), 5.95 (1H, d, J=4.5 Hz), 6.90 (1H, d, J=6.0 Hz),7.57 (5H, s)

(115)7-[2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 178° C. (dec.).

IR (Nujol): 3400-3200, 1765, 1680, 1610, 1520, 1220, 1100, 1000, 890,790 cm⁻¹

NMR (DMSO-d₆, δ): 0.9-2.0 (13H, m), 2.2 (2H, m), 2.9 (2H, m), 3.6 (2H,m), 4.0-5.1 (5H, m), 4.76 (1H, q, J=7 Hz), 5.03 (1H, d, J=5 Hz), 5.77(1H, m), 8.17 (2H, broad s), 9.45 (1H, m)

(116)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 162° to 166° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1680, 1620, 1520, 1100, 1040, 1000, 740cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (3H, d, J=6 Hz), 2.23 (2H, m), 2.90 (2H, m), 3.60(2H, m), 4.43 (4H, m), 4.90 (1H, q, J=6 Hz), 5.07 (1H, d, J=5 Hz), 5.20(2H, s), 5.77 (1H, m), 7.43 (5H, s), 8.23 (2H, m), 9.57 (1H, m)

(117)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 158° to 163° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040,1000, 960, 900, 790, 740, 720 cm⁻¹

(118) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 91° to 156° C. (dec.).

IR (Nujol): 3150, 1780, 1745, 1670, 1625, 1525 cm⁻¹

(119) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 110° to 125° C. (dec.).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 cm⁻¹

(120) pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 88° to 153° C. (dec.).

IR (Nujol): 2150, 1780, 1745, 1650, 1625, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.16 (9H, s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m),2.68 (3H, s), 3.76 (2H, broad s), 4.20 and 4.53 (2H, ABq, J=18 Hz), 4.24(2H, broad s), 5.18 (1H, d, J=4.5 Hz), 5.6-6.0 (3H, m)

(121) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 150° to 175° C. (dec.).

IR (Nujol): 3150, 1780, 1740, 1670, 1630, 1520 cm⁻¹

(122) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 96° to 155° C. (dec.).

IR (Nujol): 3300, 3150, 1775, 1730, 1670, 1625, 1530 cm⁻¹

(123) Pivaloyloxymethyl7-[2-(4-aminomethylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 160° to 168° C. (dec.).

IR (Nujol): 1780, 1745, 1670, 1628 cm⁻¹

(124) Pivaloyloxymethyl7-[2-(allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylateformate (syn isomer), mp 95° to 105° C. (dec.).

IR (Nujol): 1790, 1735, 1452, 1370, 1118, 990 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.2 (9H, s), 3.2-3.35 (2H, m), 3.7 (2H, broads), 4.2-4.6 (2H, m), 4.1-4.6 (2H, m), 4.7 (2H, broad s), 4.8-5.2 (1H,m), 5.25 (1H, d, J=4.5 Hz), 5.45 (2H, m), 5.7-6.25 (2H, m), 5.8 (1H, d,J=4.5 Hz)

(125) 1-Acetoxyethyl7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400, 3310, 3150, 1780, 1770, 1750, 1675 cm⁻¹

(126) 1-Isobutyryloxyethyl7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), amorphous powder.

IR (Nujol): 3400, 3300, 3170, 1780, 1745, 1675, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.08 (6H, d, J=7 Hz), 1.2-2.2 (14H, m), 2.2-2.9 (1H,m), 3.88 (1H, q, J=7 Hz), 4.6-5.0 (1H, m), 5.12 (1H, d, J=4.5 Hz), 5.90(1H, dd, J=4.5 and 8 Hz), 6.63 (1H, d, J=7 Hz), 8.06 (2H, broad s), 9.43(1H, d, J=8 Hz)

(127) 1-Acetoxypropyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 110° to 128° C. (dec.).

IR (Nujol): 3400, 3280, 3150, 1780, 1750, 1730, 1620 cm⁻¹

(128) 1-(2-Azidoethoxycarbonyloxy)ethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 85° to 100° C. (dec.).

IR (Nujol): 3310, 2200, 1760-1785, 1680 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.48 (3H, d, J=6 Hz), 1.5 (3H, d, J=4.5 Hz),2.0-2.5 (4H, m), 3.5-4.1 (1H, m), 3.63 (2H, t, J=4 Hz), 4.30 (2H, t, J=4Hz), 5.16 (1H, d, J=4.5 Hz), 5.2-5.45 (1H, m), 5.7-6.2 (2H, m), 6-6.2(1H, m), 6.6-6.8 (1H, m), 6.7 (1H, d, J=6 Hz)

(129) 1-Ethoxycarbonyloxyethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3420-3300, 3150, 1780, 1760, 1675, 1620 cm⁻¹

(130) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), powder, mp 66° to 75° C. (dec.).

IR (Nujol): 3300, 1780, 1745, 1680, 1620 cm⁻¹

(131) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1745, 1680, 1620 cm⁻¹

(132) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 3150, 1783, 1745, 1675, 1615 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.15 (9H, s), 1.37 (9H, s), 1.5-2.0 (2H, m),2.65 (3H, s), 2.8-3.2 (2H, m), 3.5-3.8 (2H, m), 3.9-4.3 (2H, m), 4.16and 4.53 (2H, ABq, J=13 Hz), 5.17 (1H, d, J=4.5 Hz), 5.6-6.0 (3H, m)

(133) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 88° to 101° C. (dec.).

IR (Nujol): 3300, 1780, 1750, 1675, 1620 cm⁻¹

(134) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 71° to 84° C. (dec.).

IR (Nujol): 3300, 1780, 1745, 1680, 1615 cm⁻¹

(135) Pivaloyloxymethyl7-[2-(2-cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanate(syn isomer), mp 93° to 101° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1780, 1740, 1675, 1615, 1525 cm⁻¹

(136) Phthalid-3-yl ester of7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 131° to 144° C. (dec.).

IR (Nujol): 3420, 3210, 3150, 1780, 1740, 1675, 1620, 1525 cm⁻¹

(137) Pivaloyloxymethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 111° to 124° C. (dec.).

IR (Nujol): 3400, 3300, 3270, 1775, 1740, 1670, 1620, 1520 cm⁻¹

(138) 1-Benzoyloxyethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 132° to 137° C. (dec.).

IR (Nujol): 3400, 3300, 3160, 1780, 1738, 1680, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.43 (3H, d, J=7 Hz), 1.62 (3H, d, J=5 Hz),1.7-2.4 (4H, m), 3.84 (1H, q, J=7 Hz), 5.0-5.4 (1H, m), 5.13 (1H, d,J=4.5 Hz), 5.6-6.3 (3H, m), 6.70 (1H, d, J=6 Hz), 7.16 (1H, q, J=5 Hz),7.3-8.2 (5H, m)

(139) Pivaloyloxymethyl7-[2-{4-(N-t-butoxycarbonylamino)methylbenzyloxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 cm⁻¹

(140) Pivaloyloxymethyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 cm⁻¹

(141)7-[2-{2-(N-(N-t-Butoxycarbonyl)-D-phenylglycylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 77° to 91° C. (dec.).

IR (Nujol): 3300, 3160, 1775, 1680, 1660, 1630, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.40 (3H, d, J=8 Hz), 3.1-4.2 (5H, m),5.08 (1H, d, J=4.5 Hz), 5.10 (1H, d, J=8 Hz), 5.90 (1H, dd, J=4.5 and 9Hz), 6.53 (1H, d, J=7.5 Hz), 7.32 (5H, s), 8.13 (2H, broad s), 9.48 (1H,d, J=9 Hz)

(142)7-[2-{3-(N-(2-(1-amino-1-cyclohexyl)acetyl)amino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 198° to 224° C. (dec.).

IR (Nujol): 3250, 3150, 1760, 1640,1580, 1520 cm⁻¹

(143)7-[2-{3-(N-(N-t-Butoxycarbonyl-D-phenylglycylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3200, 1775, 1700, 1650, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.3-1.6 (12H, m), 1.6-2.0 (2H, m), 2.8-3.4 (2H,m), 3.82 (1H, q, J=7.5 Hz), 3.9-4.3 (2H, m), 5.05 (1H, d, J=4.5 Hz),5.83 (1H, d, J=4.5 Hz), 6.48 (1H, d, J=6 Hz).

EXAMPLE 42

A mixture of7-[2-(1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanicacid (syn isomer) (5.7 g),1-[3-(N-t-butoxycarbonylamino)propyl]-1H-tetrazole-5-thiol (3.9 g) andsodium bicarbonate (2.5 g) in pH 6.8 phosphate buffer solution (150 ml)was stirred for 4.6 hours at 70° C. The reaction mixture was ice-cooledand washed few times with ethyl acetate. Ethyl acetate was added to anaqueous layer, and the mixture was acidified with hydrochloric acid andextracted with ethyl acetate. The extract was successively washed withwater and an aqueous solution of sodium chloride, dried over magnesiumsulfate and then evaporated. The residue was triturated with diethylether and precipitates were collected by filtration to give brown powderof7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer)(3.5 g), mp 110° to 115° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 1000, 720 cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 1.4 (12H, m), 2.02 (2H, m), 2.98 (2H, t, J=6Hz), 3.70 (2H, m), 4.1-4.5 (4H, m), 4.70 (1H, q, J=7 Hz), 5.13 (1H, d,J=5 Hz), 5.85 (1H, d, J=5 Hz)

EXAMPLE 43

The following compounds were obtained according to similar manners tothose of Examples 14 to 17 and 42.

(1)-7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 125° C. (dec.).

IR (Nujol): 3290, 3180, 1770, 1680, 1615, 1580, 1520, 1480 cm⁻¹

(2)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

IR (Nujol): 3400, 3300, 3280, 1770, 1670, 1615, 1580, 1520, 1480 cm⁻¹

(3)7-[2-(4-Chlorophenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

IR (Nujol): 3400, 3270, 3190, 1770, 1680, 1620, 1585, 1520, 1480 cm⁻¹

(4)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2-4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3400, 3300, 3190, 1765, 1700, 1620, 1580, 1540, 1520, 1480cm⁻¹

(5)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]-pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3350, 3240, 1780, 1685, 1625, 1530, 1490 cm⁻¹

(6)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° to 110° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1780, 1720, 1680, 1620, 1520 cm⁻¹

(7)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° to 110° C. (dec.).

IR (Nujol): 3360, 3220, 1785, 1690, 1625, 1525 cm⁻¹

(8)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

IR (Nujol): 3400, 3260, 3190, 2580, 1765, 1710, 1670, 1620, 1520 cm⁻¹

(9)7-[2-(Thiolan-1,1-dioxide-3-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

(10)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(11)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

IR (Nujol): 3250, 3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(12)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

(13)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1700, 1620, 1520 cm⁻¹

(14)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 220° to 225° C. (dec.).

IR (Nujol): 3300, 1700, 1680, 1605, 1520 cm⁻¹

(15)7-[2-(1-t-Butoxycarbonylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 101° to 105° C. (dec.).

IR (Nujol): 3300, 3150, 1770, 1720, 1620, 1520, 1450, 1370, 1250, 1150,1010, 900, 840, 720 cm⁻¹

(16)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 128° C. (dec.).

IR (Nujol): 3280, 3180, 1770, 1720, 1680, 1620, 1520, 1240, 1150, 1000,740, 720 cm⁻¹

(17)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 115° to 120° C. (dec.).

IR (Nujol): 3280, 3170, 1780, 1720, 1680, 1520, 1140, 990, 750 cm⁻¹

(18)7-[2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 143° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1670, 1620, 1520, 1245, 1150, 1060,995, 840 cm⁻¹

(19)7-[2-(1-Methyl-1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 96° to 100° C. (dec.).

IR (Nujol): 3300, 3150, 1780, 1680, 1570, 1240, 1160, 990 cm⁻¹

(20)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 96° to 100° C. (dec.).

IR (Nujol): 3300, 3150, 1780, 1720, 1680, 1620, 1520, 1240, 1150, 1090,1000 cm⁻¹

(21)7-[2-(1-Phenylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 175° C.

IR (Nujol): 3400, 3250, 3150, 1750, 1650, 1610, 1520, 1400, 1240, 1160,1060, 1000, 700 cm⁻¹

(22)7-[2-(p-Tolyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 150° C., which is a mixturewith o-tolyl isomer.

IR (Nujol): 3350, 3250, 1780, 1680, 1630, 1530, 1510, 1230, 1050, 910,820 cm⁻¹

(23)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 155° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060,980, 930, 700 cm⁻¹

(24)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 170° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1320, 1160, 1120, 1060,930, 790, 700 cm⁻¹

(25)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 170° C.

IR (Nujol): 3450, 3350, 3200, 1780, 1710, 1680, 1610, 1510, 1590, 1240,1200, 1170, 1090, 990, 910, 840 cm⁻¹

(26)7-[2-(2,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 165° C.

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1230, 1100, 1060,960, 910, 810 cm⁻¹

(27)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3200, 3160, 1773, 1685, 1620 cm⁻¹

(28)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3200, 3160, 1775, 1720, 1700, 1675, 1620 cm⁻¹

(29)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1775, 1710, 1700, 1670, 1650, 1620 cm⁻¹

(30)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 81° to 119° C. (dec.).

IR (Nujol): 3300, 3180, 1773, 1715, 1700, 1670, 1620 cm⁻¹

(31)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N,N-dimethylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 173° C. (dec.).

IR (Nujol): 3400, 3280, 3150, 1760, 1665, 1610, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 2.53 (6H, s), 3.07-3.37 (2H, m), 3.50-3.77 (2H,m), 4.10-4.37 (2H, m), 4.43-4.83 (4H, m), 5.10 (1H, d, J=5 Hz), 5.80(1H, d, J=5 Hz)

(32)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N,N-dimethylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 3280, 3160, 1760, 1665, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.10-2.43 (2H, m), 2.70 (6H, s), 2.92-3.28 (2H, m),3.45-3.80 (2H, m), 4.17-4.80 (6H, m), 5.10 (1H, d, J=5 Hz), 5.84 (1H,dd, J=5 and 8 Hz), 8.15 (2H, broad s), 10.1 (1H, d, J=8 Hz)

(33)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 85° to 90° C. (dec.).

IR (Nujol): 3400, 3290, 3200, 1770, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (9H, s), 1.77-2.17 (2H, m), 2.78-3.23 (2H, m),3.50 (1H, t, J=2 Hz), 3.73 (2H, broad s), 4.07-4.53 (4H, m), 4.82 (2H,d, J=2 Hz), 5.15 (1H, d, J=5 Hz), 5.85 (1H, dd, J=5 and 8 Hz), 8.17 (2H,broad s), 9.65 (1H, d, J=8 Hz)

(34)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33 (9H, s), 1.67-2.12 (2H, m), 2.77-3.07 (2H, m),3.63 (2H, broad s), 4.07-4.43 (4H, m), 4.60 (2H, s), 5.05 (1H, d, J=4Hz), 5.77 (1H, dd, J=4 and 8 Hz), 8.08 (2H, s), 9.47 (1H, d, J=8 Hz)

(35)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 132° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆ δ): 3.73 (2H, broad s), 4.30 and 4.53 (2H, ABq, J=14 Hz),4.73 and 4.97 (2H, ABq, J=8 Hz), 5.10 (1H, d, J=4 Hz), 5.35 (2H, s),5.87 (1H, dd, J=4 and 8 Hz), 8.23 (2H, s), 9.80 (1H, d, J=8 Hz)

(36)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 192° to 195° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1680, 1520, 1450, 1360, 1240, 1160, 1020,730 cm⁻¹

NMR (DMSO-d₆, δ): 0.98 (6H, d, J=7 Hz), 1.38 (9H, s), 1.8-2.2 (3H, m),2.8-3.2 (2H, m), 3.7 (2H, m), 4.1-4.7 (5H, m), 5.12 (1H, d, J=5 Hz),5.7-6.9 (1H, m), 6.7-6.9 (1H, m), 8.03 (2H, broad s), 9.42 (1H, d, J=8Hz)

(37)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 192° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1450, 1360, 1250, 1160,1000, 730-710 cm⁻¹

NMR (DMSO-d₆, δ): 1.08 (3H, t, J=7 Hz), 1.35 (9H, s), 1.6-2.1 (4H, m),2.6-3.1 (2H, m), 3.7 (2H, m), 4.1-4.6 (5H, m), 5.10 (1H, d, J=6 Hz),5.81 (1H, dd, J=5 and 8 Hz), 6.8 (1H, m), 8.10 (2H, broad s), 9.45 and9.47 (1H, d, J=8 Hz)

(38)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1775, 1715, 1675, 1650, 1615 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.37 (18H, s), 1.5-2.1 (4H, m), 2.7-3.3 (4H, m),3.5-3.9 (2H, m), 3.9-4.5 (6H, m), 5.13 (1H, d, J=4.5 Hz), 5.83 (1H, d,J=4.5 Hz)

(39)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 110° to 115° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1600, 1520, 1250, 1000, 720 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.4 (12H, m), 2.02 (2H, m), 2.98 (2H, t, J=6Hz), 3.70 (2H, m), 4.1-4.5 (4H, m), 4.70 (1H, q, J=7 Hz), 5.13 (1H, d,J=5 Hz), 5.85 (1H, d, J=5 Hz)

(40)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 205° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1520, 1250, 1160, 1000 cm⁻¹

NMR (DMSO-d₆, δ): 1.38 (9H, s), 1.68 (4H, m), 2.0 (6H, m), 2.96 (2H, m),3.70 (2H, m), 4.26 (4H, m), 5.12 (1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and8 Hz), 6.86 (1H, m), 8.14 (2H, m), 9.40 (1H, d, J=8 Hz)

(41)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-morpholinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 194° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1610, 1530, 1240, 1180, 1090, 1060,880, 760 cm⁻¹

NMR (DMSO-d₆, δ): 2.17 (2H, m), 2.63 (6H, m), 3.67 (6H, m), 4.37 (4H,m), 4.67 (2H, broad s), 5.15 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and 8Hz), 8.17 (2H, m), 9.73 (1H, d, J=8 Hz)

(42)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1770, 1680, 1520, 1240, 1160, 990 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (15H, broad s), 2.0 (2H, m), 3.0 (2H, m), 3.77(2H, m), 4.10-4.40 (4H, m), 5.20 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and8 Hz), 6.87 (1H, m), 8.20 (2H, broad s), 9.47 (1H, d, J=8 Hz)

(43)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 214° C. (dec.).

IR (Nujol): 3250, 3180, 1760, 1720-1660, 1590, 1520, 1240, 1090, 1050,720 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.30 (3H, s), 3.65 (2H, m), 4.10 (2H, m), 4.65(2H, broad s), 5.11 (1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and 8 Hz)

(44)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{4-(N-t-butoxycarbonylamino)butyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1240, 1160, 1090, 1060,890 cm⁻¹

NMR (DMSO-d₆, δ): 1.0-2.0 (4H, m), 1.33 (9H, s), 2.90 (2H, m), 3.66 (2H,m), 4.0-4.5 (4H, m), 4.62 (2H, broad s), 5.10 (1H, d, J=5 Hz), 5.80 (1H,dd, J=5 and 8 Hz), 6.75 (1H, m), 8.13 (2H, broad s), 9.55 (1H, d, J=8Hz)

(45)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-piperidinopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylica acid (syn isomer), mp 223° to 228° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.30-1.83 (6H, m), 2.1-2.3 (2H, m), 2.8-3.3 (6H, m),3.60 (2H, broad s), 4.0-4.50 (4H, m), 4.60 (2H, s), 5.06 (1H, d, J=4Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.15 (2H, s), 10.1 (1H, d, J=8 Hz)

(46)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3300, 3200, 1765, 1720, 1660, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.67 (2H, broad s), 4.27 and 4.47 (2H, ABq, J=13 Hz),4.67 (2H, s), 5.13 (1H, d, J=4 Hz), 5.33 (2H, s), 5.87 (1H, dd, J=4 and8 Hz), 8.20 (2H, s), 9.60 (1H, d, J=8 Hz)

(47)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{6-(N-t-butoxycarbonylamino)hexyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), pale yellow powder.

(48)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[5-(N-t-butoxycarbonylamino)methyl-1,3,4-thiadiazol-2-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 215° C. (dec.).

IR (Nujol): 3300, 1770, 1680, 1620, 1520, 1240, 1140 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (12H, broad s), 3.70 (2H, m), 4.27-4.87 (5H, m),5.20 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.70 (1H, m), 8.17(2H, broad s), 9.50 (1H, d, J=8 Hz)

(49)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3450, 3300, 3210, 1770, 1670, 1620, 1525 cm⁻¹

(50)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1660, 1640, 1520 cm⁻¹

(51)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 189° C. (dec.).

IR (Nujol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230,1180, 1100, 1020, 900, 730 cm⁻¹

(52)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 188° C. (dec.).

IR (Nujol): 3400-1350, 1770, 1670, 1620, 1530, 1380, 1280, 1230, 1180,1100, 1050, 1010, 730 cm⁻¹

(53)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720 cm⁻¹

(54)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(4-aminobutyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 191° to 194° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890,740, 720 cm⁻¹

(55)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 203° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1160, 990 cm⁻¹

(56)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 202° to 205° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730cm⁻¹

(57)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 207° to 210° C. (dec.).

Ir (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1170, 1090, 1060,1040, 990 cm⁻¹

(58)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(6-aminohexyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1670, 1620, 1520, 1240, 1180, 1060 cm⁻¹

(59)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 183° C. (dec.).

IR (Nujol): 3150, 1765, 1660, 1630, 1570, 1520 cm⁻¹

(60)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 185° C. (dec.).

IR (Nujol): 3140, 1760, 1660, 1610, 1580, 1520 cm⁻¹

(61)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 192° to 195° C. (dec.).

IR (Nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 cm⁻¹

(62)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 184° C. (dec.).

IR (Nujol): 3160, 1760, 1660, 1590 cm⁻¹

(63)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

Ir (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 cm⁻¹

(64)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520 cm⁻¹

(65)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 195° C. (dec.).

IR (Nujol): 3400, 3300, 3150, 1765, 1670, 1610, 1520 cm⁻¹

(66)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm⁻¹

(67)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 153° to 158° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1670, 1620, 1520, 1220, 1060, 1000,900, 730 cm⁻¹

(68)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 168° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000,900, 720 cm⁻¹

(69)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 164° to 167° C. (dec.).

IR (Nujol): 3300, 3200, 2800-2300, 1770, 1720-1660, 1620, 1520, 1160,1060, 990, 800 cm⁻¹

(70)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 169° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1660, 1620, 1520, 1240, 1180, 1060,1000, 720 cm⁻¹

(71)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 180° C.

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1520, 1260, 1100, 1040, 1000cm⁻¹

(72)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, 1170, 990 cm⁻¹

(73)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3300, 1770, 1650, 1610, 1520 cm⁻¹

(74)7-[2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1680, 1620, 1525 cm⁻¹

(75)7-[2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3400-3250, 1780, 1680, 1620, 1520, 1240, 1220, 1160, 1100,1000, 740, 720 cm⁻¹

(76)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 113° to 117° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1520, 1250, 1160, 1100, 1040,1000, 740, 700 cm⁻¹

(77)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 149° to 155° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1700, 1620, 1520, 1250, 1160, 1100, 1040,1000, 740, 720 cm⁻¹

(78)7-[2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 178° C. (dec.).

IR (Nujol): 3400-3200, 1765, 1680, 1610, 1520, 1220, 1100, 1000, 890,790 cm⁻¹

(79)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 162° to 166° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1680, 1620, 1520, 1100, 1040, 1000, 740cm⁻¹

(80)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 158° to 163° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040,1000, 960, 900, 790, 740, 720 cm⁻¹

(81) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 110° to 125° C. (dec.).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 cm⁻¹

(82) Pivaloyloxymethyl7-[2-(3-amiopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 88° to 153° C. (dec.).

IR (Nujol): 2150, 1780, 1745, 1650, 1625, 1525 cm⁻¹

(83) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 150° to 175° C. (dec.).

IR (Nujol): 3150, 1780, 1740, 1670, 1630, 1520 cm⁻¹

(84) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 96° to 155° C. (dec.).

IR (Nujol): 3300, 3150, 1775, 1730, 1670, 1625, 1530 cm⁻¹

(85) Pivaloyloxymethyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylateformate (syn isomer), mp 95° to 105° C. (dec.).

IR (Nujol): 1790, 1735, 1452, 1370, 1118, 990 cm⁻¹

(86) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1745, 1680, 1620 cm⁻¹

(87) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 3150, 1783, 1745, 1675, 1615 cm⁻¹

(88) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 88° to 101° C. (dec.).

IR (Nujol): 3300, 1780, 1750, 1675, 1620 cm⁻¹

(89) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 71° to 84° C. (dec.).

IR (Nujol): 3300, 1780, 1745, 1680, 1615 cm⁻¹

(90) Pivaloyloxymethyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 cm⁻¹

(91)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1520 cm⁻¹

(92)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

(93)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

I.R. (Nujol): 3400, 3200, 1770, 1700, 1660, 1620, 1580, 1510 cm⁻¹

(94)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.)

I.R. (Nujol): 3450, 3350, 3180, 1780, 1710, 1680, 1610, 1590, 1510 cm⁻¹

(95)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 158° C. (dec.)

I.R. (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1620, 1590, 1520 cm⁻¹

(96)7-[2-(2-Methoxy-5-nitrophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 169° C. (dec.)

I.R. (Nujol): 3380, 3220, 3100, 1780, 1690, 1620, 1600, 1520, 1340,1280, 1085, 1065, 820, 750 cm⁻¹

(97)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1670, 1615, 1520, 1495 cm⁻¹

(98)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3450, 3280, 3180, 1760, 1720, 1660, 1620, 1580, 1520, 1480cm⁻¹

(99)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3250, 3170, 1765, 1700, 1680, 1650, 1615, 1580,1510, 1480 cm⁻¹

(100)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 120° to 125° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1670, 1615, 1580, 1520, 1480 cm⁻¹

(101)7-[2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 160° C.

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520, 1250, 1205, 1060 cm⁻¹

(102)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 164° C.

I.R. (Nujol): 3300, 3180, 1765, 1670, 1610, 1520, 1320, 1165, 1120,1060, 930, 790, 700 cm⁻¹

(103)7-[2-(3-Ethoxycarbonylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), decomposed by 162° C.

I.R. (Nujol): 3350-3150, 1770, 1720-1660, 1620, 1520, 1290, 1270, 1100,1060, 900, 760 cm⁻¹

(104)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1610, 1520 cm⁻¹

(105)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1670, 1620, 1520, 1500 cm⁻¹

(106)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-carboxymethyl-3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-b]pyridazin-6-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1710, 1620, 1540, 1520, 1500 cm⁻¹

(107)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1700, 1620, 1520, 1500 cm⁻¹

(108)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3450, 3350, 3150, 1780, 1705, 1670, 1610, 1510 cm⁻¹

(109)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3250, 1760, 1670, 1620, 1590, 1520 cm⁻¹

(110)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1770, 1720, 1680, 1620, 1525 cm⁻¹

(111)7-[2-{3-(N-t-Butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 107° to 112° C. (dec.).

(112)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1520 cm⁻¹

(113)7-[2(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1525 cm⁻¹

(114)7-[2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 181° to 186° C. (dec.).

I.R. (Nujol): 3320,1780, 1680, 1620, 1520, 1165 cm⁻¹

(115)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 147° to 161° C. (dec.).

I.R. (Nujol): 3420, 1780, 1680, 1615, 1525 cm⁻¹

(116)7-[2-{2-(N-t-Butoxycarbonylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 105° C. (dec.).

I.R. (Nujol): 3305, 3160, 1770,1670, 1520, 1245 cm⁻¹

(117)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 3175, 1770, 1720, 1680, 1620, 1520 cm⁻¹

(118)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

I.R. (Nujol): 3400, 3280, 3180, 1770, 1720, 1680, 1620, 1520 cm⁻¹

(119)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 110° to 115° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1680, 1620, 1520 cm⁻¹

(120)7-[2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-phenyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1775, 1720, 1685, 1620, 1525, 1500 cm⁻¹

(121)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 184° to 196° C. (dec.).

I.R. (Nujol): 3400-3100, 1760, 1660, 1610, 1520, 1170, 1060, 1010 cm⁻¹

(122)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 190° to 198° C. (dec.).

I.R. (Nujol): 3250, 3160, 1760, 1650, 1615, 1522, 1020 cm⁻¹

(123)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1710, 1680, 1610, 1520 cm⁻¹

(124)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1765, 1720, 1680, 1620, 1520 cm⁻¹

(125)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520 cm⁻¹

(126)7-[2-(2-Aminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 182° to 187° C. (dec.).

I.R. (Nujol): 3350, 3150, 1760, 1660, 1625, 1565, 1520 cm⁻¹

(127)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3250, 1755, 1660, 1590, 1520 cm⁻¹

(128)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

I.R. (Nujol): 3300, 3170, 1760, 1670, 1615, 1500 cm⁻¹

(129)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-phenyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3400, 3300, 3180, 1765, 1720, 1680, 1615, 1520, 1495 cm⁻¹

(130)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 153° to 162° C. (dec.).

I.R. (Nujol): 3260, 3160, 1763, 1665, 1608, 1520 cm⁻¹

(131) Pivaloyloxymethyl7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), mp 132° to 135° C. (dec.).

I.R. (Nujol): 3270, 3160, 1775, 1745, 1675, 1610, 1520, 1115 cm⁻¹

EXAMPLE 44

A solution of7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(N-t-butoxycarbonylamino)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (3.4 g) in formic acid (34 ml) was stirred for 2 hoursat ambient temperature. The reaction mixture was post-treated in aconventional manner to give7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.1 g), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1000, 720 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.48 (3H, d, J=7 Hz), 2.3 (2H, m), 2.9 (2H, m),3.6 (2H, m), 4.1-5.0 (4H, m), 4.70 (1H, q, J=7 Hz), 5.10 (1H, d, J=5Hz), 5.85 (1H, m)

EXAMPLE 45

A solution of pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer) (2.7 g), anisole (24 drops) and 0.6 N hydrochloric acid(26.6 ml) in dioxane (18 ml) was stirred for 30 minutes at ambienttemperature. An insoluble material was collected by decantation, anddissolved in water. The aqueous solution was washed twice with ethylacetate and then lyophilized to give pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer) (1.8 g), mp 90° to 155° C. (dec.).

IR (Nujol): 3300, 3150, 1775, 1730, 1670, 1625, 1530 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.20 (9H, s), 1.9-2.5 (2H, m), 2.9-3.5 (2H, m),3.78 (2H, broad s), 4.27 and 4.63 (2H, ABq, J=14 Hz), 4.2-4.8 (2H, m),5.25 (1H, d, J=2.5 Hz), 5.6-6.1 (3H, m), 9.42 (1H, s)

EXAMPLE 46

The following compounds were obtained according to similar manners tothose of Examples 22 to 25, 44 and 45.

(1)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3450, 3300, 3210, 1770, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.90-2.37 (2H, m), 2.67-3.03 (2H, m), 3.47 (1H, t, J=2Hz), 3.37-3.53 (2H, m), 3.93-4.60 (4H, m), 4.75 (2H, d, J=2 Hz), 5.0(1H, d, J=5 Hz), 5.68 (1H, dd, J=5 and 8 Hz), 8.12 (2H, broad s), 9.50(1H, d, J=8 Hz)

(2)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1660, 1640, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.30 (2H, m), 2.73-3.0 (2H, m), 3.60 (2H, broads), 4.20-4.50 (4H, m), 4.60 (2H, s), 5.08 (1H, d, J=4 Hz), 5.83 (1H, dd,J=4 and 8 Hz), 8.23 (2H, s), 10.20 (1H, d, J=8 Hz)

(3)7[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 189° C. (dec.).

IR (Nujol): 3400-3100, 3150, 1770, 1670, 1620, 1520, 1380, 1280, 1230,1180, 1100, 1020, 900, 730 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.98 (6H, d, J=7 Hz), 2.2 (3H, m), 3.6 (2H, m),3.9 (2H, m), 4.3 (5H, m), 5.06 (1H, d, J=5 Hz), 5.70 (1/2H, d, J=5 Hz),5.82 (1/2H, d, J=5 Hz)

(4)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 183° to 188° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1530, 1380, 1280, 1230, 1180,1100, 1050, 1010, 730 cm⁻¹

NMR (DMSO-d₆, δ): 0.98 (3H, t, J=7 Hz), 1.7-2.3 (4H, m), 2.7-3.1 (2H,m), 3.4-3.7 (2H, m), 4.2-4.8 (5H, m), 5.07 (1H, d, J=5 Hz), 5.6-5.9 (1H,m), 8.13 (2H, broad s), 10.08 (1H, m)

(5)7[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(4-aminobutyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 191° to 194° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1670, 1620, 1520, 1230, 1170, 1050, 890,740, 720 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.2-2.1 (4H, m), 2.80 (2H, t, J=6 Hz), 3.6 (2H,m), 4.3 (4H, m), 4.60 (2H, broad s), 5.10 (1H, d, J=5 Hz), 5.82 (1H, d,J=5 Hz)

(6)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 203° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1160, 990 cm⁻¹

NMR (DMSO-d₆, δ): 1.50 (6H, s), 2.20 (2H, m), 2.90 (2H, m), 3.60 (2H,m), 4.30 (4H, m), 5.10 (1H, d, J=5 Hz), 5.83 (1H, m), 8.20 (2H, broads), 9.87 (1H, d, J=8 Hz)

(7)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 202° to 205° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1660, 1620, 1520, 1180, 1060, 1000, 730cm⁻¹

NMR (DMSO-d₆, δ): 1.70 (4H, m), 2.10 (6H, m), 2.90 (2H, m), 3.11 and3.60 (2H, ABq, J=18 Hz), 4.40 (4H, m), 5.08 (1H, d, J=5 Hz), 5.80 (1H,dd, J=5 and 8 Hz), 8.23 (2H, m), 9.78 (1H, m)

(8)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-aminomethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 207° to 210° C. (dec.).

IR (Nujol): 3300, 3150, 1760, 1660, 1620, 1520, 1230, 1170, 1090, 1060,1040, 990 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.43 (3H, d, J=5 Hz), 3.60 (2H, m), 4.0-4.93(5H, m), 5.05 and 5.15 (1H, d, J=5 Hz), 5.70 (1H, m), 8.1 (2H, broad s),9.5 (1H, d, J=8 Hz)

(9)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido-3-[1-(6-aminohexyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 188° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1670, 1620, 1520, 1240, 1180, 1060 cm⁻¹

NMR (DMSO-d₆, δ): 1.10-1.57 (6H, m), 1.57-1.97 (2H, m), 2.70 (2H, m),3.83 (2H, m), 4.27 (4H, m), 4.57 (2H, broad s), 5.03 (1H, d, J=5 Hz),5.72 (1H, dd, J=5 and 8 Hz), 8.13 (2H, m), 9.80 (1H, d, J=8 Hz)

(10)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 183° C. (dec.).

IR (Nujol): 3150, 1765, 1660, 1630, 1570, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.6-2.3 (2H, m), 2.6-3.2 (2H, m), 3.2-3.7 (2H,m), 3.9-4.7 (4H, m), 4.97 (1H, d, J=4.5 Hz), 5.68 (1H, d, J=4.5 Hz),9.50 (1H, s)

(11)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 185° C. (dec.).

IR (Nujol): 3140, 1760, 1660, 1610, 1580, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.6-2.4 (2H, m), 2.7-3.4 (2H, m), 3.3-3.9 (4H,m), 3.9-4.7 (6H, m), 4.97 (1H, d, J=4.5 Hz), 5.67 (1H, d, J=5 Hz)

(12)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 192° to 195° C. (dec.).

IR (Nujol): 3250, 3140, 1760, 1640, 1620, 1585, 1525 cm⁻¹

NMR (D₂ O+DCl, δ): 2.0-3.4 (2H, m), 3.00 (3H, s), 3.22 (2H, t, J=7 Hz),3.74 and 3.92 (2H, ABq, J=18 Hz), 4.36 and B 4.53 (2H, ABq, J=14 Hz),4.54 (2H, t, J=7 Hz), 5.28 (1H, d, J=4.5 Hz), 5.82 (1H, d, J=4.5 Hz)

(13)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 184° C. (dec.).

IR (Nujol): 3160, 1760, 1660, 1590 cm⁻¹

NMR (D₂ O+DCl, δ): 1.9-2.4 (2H, m), 3.20 (3H, t, J=8 Hz), 3.80 (2H,broad s), 4.02 (3H, s), 4.22 (2H broad s), 4.52 (2H, t, J=6 Hz), 5.25(1H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz)

(14)7-[2-(4-Aminomethylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid formate (syn isomer), mp 230° to 240° C. (dec.).

IR (Nujol): 1750 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.86 (3H, s), 3.25 (2H, m), 3.97 (2H, s), 4.94(1H, d, J=4.5 Hz), 5.16 (2H, s), 5.6 (1H, d, J=4.5 Hz), 7.35 (4H, s),8.20 (1H, s)

(15)7-[2-(3-Aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3150, 1760, 1660, 1607, 1595, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 2.0-2.7 (4H, m), 3.0-3.5 (4H, m), 3.4-4.0 (2H,m), 4.0-4.9 (6H, m), 5.20 (1H, d, J=4.5 Hz), 5.81 (1H, d, J=4.5 Hz)

(16)7-[2-(2-D-Phenylglycylaminoethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 204° to 222° C. (dec.).

IR (Nujol): 3260, 3150, 1760, 1665, 1615, 1512, 1400, 1045 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.43 (3H, d, J=7 Hz), 3.13-4.45 (5H, m), 4.98(1H, s), 5.02 (1H, d, J=4.5 Hz), 5.85 (1H, d, J=4.5 Hz), 6.27 (1H, d,J=6 Hz), 7.43 (5H, s)

(17)7-[2-(3-D-Phenylglycylaminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 203° to 231° C. (dec.).

IR (Nujol): 3280, 1170, 1760, 1660, 1600, 1520, 1400 cm⁻¹

NMR (D₂ O+DCl, δ): 1.47 (3H, d, J=7.5 Hz), 1.7-2.3 (2H, m), 3.40 (2H, t,J=7 Hz), 3.88 (1H, q, J=7.5 Hz), 4.33 (2H, t, J=6 Hz), 5.18 (1H, d,J=4.5 Hz), 5.20 (1H, s), 5.95 (1H, d, J=4.5 Hz), 6.90 (1H, d, J=6.0 Hz),7.57 (5H, s)

(18)7-[2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 178° C. (dec.).

IR (Nujol): 3400-3200, 1765, 1680, 1610, 1520, 1220, 1100, 1000, 890,790 cm⁻¹

NMR (DMSO-d₆, δ): 0.9-2.0 (13H, m), 2.2 (2H, m), 2.9 (2H, m), 3.6 (2H,m), 4.0-5.1 (5H, m), 4.76 (1H, q, J=7 Hz), 5.03 (1H, d, J=5 Hz), 5.77(1H, m), 8.17 (2H, broad s), 9.45 (1H, m)

(19)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 162° to 166° C. (dec.).

IR (Nujol): 3300, 3200, 1760, 1680, 1620, 1520, 1100, 1040, 1000, 740cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (3H, d, J=6 Hz), 2.23 (2H, m), 2.90 (2H, m), 3.60(2H, m), 4.43 (4H, m), 4.90 (1H, q, J=6 Hz), 5.07 (1H, d, J=5 Hz), 5.20(2H, s), 5.77 (1H, m), 7.43 (5H, s), 8.23 (2H, m), 9.57 (1H, m)

(20)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 158° to 163° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1680, 1610, 1530, 1300, 1290, 1050, 1040,1000, 960, 900, 790, 740, 720 cm⁻¹

NMR (DMSO-d₆, δ): 0.85 (3H, t, J=6 Hz), 1.1-1.8 (4H, m), 1.43 (3H, d,J=6 Hz), 1.9-2.4 (2H, m), 2.7-3.1 (2H, m), 3.5 (2H, m), 3.9-4.4 (2H, m),4.10 (2H, t, J=6 Hz), 4.3-4.6 (2H, m), 4.78 (1H, q, J=7 Hz), 5.02 (1H,d, J=5 Hz), 5.7 (1H, m), 8.2 (2H, broad s), 10.1 (1H, m)

(21) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 91° to 156° C. (dec.)

IR (Nujol): 3150, 1780, 1745, 1670, 1625, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.13 (9H, s), 1.43 (3H, d, J=7 Hz), 1.7-2.3 (2H,m), 2.5-3.2 (2H, m), 3.5-4.5 (3H, m), 5.10 (1H, d, J=5 Hz), 5.6-6.1 (3H,m), 6.63 (1H, d, J=7 Hz)

(22) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 110° to 125° C. (dec.).

IR (Nujol): 1780, 1745, 1670, 1625, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.13 (9H, s), 1.7-2.3 (2H, m), 2.6-3.2 (2H, m),3.75 (2H, broad s), 3.90 (3H, s), 4.0-4.7 (4H, m), 5.12 (1H, d, J=4.5Hz), 5.6-6.1 (3H, m)

(23) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 88° to 153° C. (dec.)

IR (Nujol): 2150, 1780, 1745, 1650, 1625, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.16 (9H, s), 1.6-2.2 (2H, m), 2.6-3.1 (2H, m),2.68 (3H, s), 3.76 (2H, broad s), 4.20 and 4.53 (2H, ABq, J=18 Hz), 4.24(2H, broad s), 5.18 (1H, d, J=4.5 Hz), 5.6-6.0 (3H, m)

(24) Pivaloyloxymethyl7-[2-(3-aminopropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 150° to 175° C. (dec.).

IR (Nujol): 3150, 1780, 1740, 1670, 1630, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.20 (9H, s), 1.7-2.3 (2H, m), 2.6-3.2 (2H, m),3.5-4.0 (4H, m), 4.0-4.6 (6H, m), 5.17 (1H, d, J=5Hz), 5.6-6.1 (3H, m)

(25) Pivaloyloxymethyl7-[2-(4-aminomethylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylatehydrochloride (syn isomer), mp 160° to 168° C. (dec.).

IR (Nujol): 1780, 1745, 1670, 1628 cm⁻¹

(26) Pivaloyloxymethyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylateformate (syn isomer), mp 95° to 105° C. (dec.).

IR (Nujol): 1790, 1735, 1452, 1370, 1118, 990 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.2 (9H, s), 3.2-3.35 (2H, m), 3.7 (2H, broads), 4.2-4.6 (2H, m), 4.1-4.6 (2H, m), 4.7 (2H, broad s), 4.8-5.2 (1H,m), 5.25 (1H, d, J=4.5 Hz), 5.45 (2H, m), 5.7-6.25 (2H, m), 5.8 (1H, d,J=4.5 Hz)

EXAMPLE 47

A mixture of7-[2-(1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (2.35 g), trifluoroacetic acid (16 ml) and anisole (3ml) was stirred for 40 minutes at ambient temperature. The reactionmixture was evaporated and the residue was triturated with diisopropylether and washed with diisopropyl ether to give white powder of7-[2-(1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (2.3 g). The powder (2.3 g) was reprecipitated from amixture of sodium bicarbonate (0.44 g) in water (50 ml) and precipitateswere collected by filtration and washed with water to give pale brownpowder of the same compound (1.1 g), mp 230° to 235° C. (dec.).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240,1170, 970, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.46 (3H, d, J=8 Hz), 3.46 (2H, m), 4.72 (1H, q, J=7Hz), 5.15 (1H, d, J=5 Hz), 5.58 (1H, dd, J=5 and 8 Hz), 6.50 (1H, m),8.20 (2H, m), 9.40 and 9.57 (1H, d, J=8 Hz)

EXAMPLE 48

A mixture of7-[2-(α-t-butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (3.0 g), trifluoroacetic acid (30 ml) and anisole (6ml) was stirred for 1 hour at ambient temperature. The reaction mixturewas post-treated in a conventional manner to give7-[2-(α-carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.16 g), mp 190° to 195° C. (dec.).

IR (Nujol): 3400, 3300, 3150, 1765, 1670, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.10-3.77 (4H, m), 4.13-4.37 (2H, m), 4.40-4.77 (2H,m), 5.0-5.23 (1H, m), 5.57 (1/2H, s), 5.65 (1/2H, s), 5.53-5.93 (1H, m),7.27-7.80 (5H, m), 8.28 (2H, broad s)

EXAMPLE 49

The following compounds were obtained according to similar manners tothose of Examples 27, 47 and 48.

(1)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3400, 3290, 3160, 2500, 1770, 1720, 1615, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.12-3.88 (2H, m), 4.08-4.68 (2H, m), 5.04 (1/2H, d,J=5 Hz), 5.10 (1/2H, d, J=5 Hz), 5.62 (1H, s), 5.64-5.88 (1H, m),7.12-7.68 (5H, m), 8.14 (2H, broad s), 9.52 (1/2H, s), 9.54 (1/2H, s),9.36-9.72 (1H, m)

(2)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 3.24-3.68 (2H, m), 5.02 (1/2H, d, J=5 Hz), 5.08 (1/2H,d, J=5 Hz), 5.64 (1H, s), 5.68-5.96 (1H, m), 6.28-6.60 (1H, m),7.16-7.64 (5H, m), 8.16 (2H, broad s), 9.54 (1/2H, d, J=8 Hz), 9.62(1/2H, d, J=8 Hz)

(3)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

IR (Nujol): 3350, 3250, 1770, 1720, 1680, 1630, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 3.53 (2H, d, J=3 Hz), 4.63 (2H, s), 5.07 (1H, d, J=4Hz), 5.85 (1H, dd, J=4 and 8 Hz), 6.45 (1H, t, J=3 Hz), 8.13 (2H, s),9.50 (1H, d, J=8 Hz)

(4)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{3-(4-methyl-1-piperazinyl)propyl}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 185° to 190° C. (dec.).

IR (Nujol): 3300, 1760, 1670, 1600, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.80-2.10 (2H, m), 2.30-2.50 (4H, m), 2.60 (3H, s),2.8-3.3 (6H, m), 3.60 (2H, broad s), 4.20-4.50 (4H, m), 4.60 (2H, s),5.10 (1H, d, J=4 Hz), 5.83 (1H, dd, J=4 and 8 Hz), 8.15 (2H, s), 10.17(1H, d, J=8 Hz)

(5)7-[2-(1-Carboxy-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-cephalosporanicacid (syn isomer).

IR (Nujol): 3400-3150, 1770, 1730-1670, 1720, 1620, 1460, 1370, 1230,1030, 730 cm⁻¹

NMR (DMSO-d₆, δ): 0.97 (6H, d, J=7 Hz), 2.03 (3H, s), 1.9-2.3 (1H, m),3.6 (2H, m), 4.27 and 4.35 (1H, d, J=6 Hz), 4.65 and 5.02 (2H, ABq, J=13Hz), 5.15 (1H, d, J=5 Hz), 5.7-6.0 (1H, m), 8.03 (2H, broad s), 9.42(1H, d, J=8 Hz)

(6)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 153° to 158° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1670, 1620, 1520, 1220, 1060, 1000,900, 730 cm⁻¹

NMR (DMSO-d₆, δ): 0.97 (3H, t, J=7 Hz), 1.83 (2H, m), 3.56 and 3.80 (2H,ABq, J=18 Hz), 4.25 and 4.55 (2H, ABq, J=14 Hz), 4.52 (1H, t, J=7 Hz),5.14 (1H, d, J=5 Hz), 5.82 (1H, dd, J=5 and 8 Hz), 8.1 (2H, broad s),9.46 (1H, d, J=8 Hz), 9.52 (1H, s)

(7)7-[2-(1-Carboxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer), mp 115° to 120° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1720-1670, 1620, 1520, 1230,1030-1010, 890, 740-720 cm⁻¹

NMR (DMSO-d₆, δ): 1.07 (3H, t, J=6 Hz), 1.8 (2H, m), 2.00 (3H, s), 3.5(2H, m), 4.63 and 5.02 (2H, ABq, J=14 Hz), 4.5 (1H, m), 5.14 (2H, d, J=5Hz), 5.84 (1H, dd, J=5 and 9 Hz), 8.11 (2H, broad s), 9.5 (1H, m)

(8)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 168° C. (dec.).

IR (Nujol): 3400-3200, 1770, 1710, 1670, 1620, 1520, 1230, 1170, 1000,900, 720 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (3H, d, J=7 Hz), 3.7 (2H, m), 4.23 and 4.60 (2H,ABq, J=14 Hz), 4.68 (1H, q, J=7 Hz), 5.15 (1H, d, J=5 Hz), 5.83 (1H, dd,J=5 and 8 Hz), 8.1 (2H, broad s), 9.3-9.6 (1H, m), 9.50 (1H, s)

(9)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 164° to 167° C. (dec.).

IR (Nujol): 3300, 3200, 2800-2300, 1770, 1720-1660, 1620, 1520, 1160,1060, 990, 800 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (6H, s), 3.53 and 3.87 (2H, ABq, J=20 Hz), 4.24and 4.63 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=5 Hz), 5.83 (1H, dd, J=5 and8 Hz), 8.2 (2H, broad s), 9.44 (1H, d, J=8 Hz), 9.50 (1H, s)

(10)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 169° C. (dec.).

IR (Nujol): 3300, 3180, 1770, 1720-1660, 1620, 1520, 1240, 1180, 1060,1000, 720 cm⁻¹

NMR (DMSO-d₆, δ): 1.8 (4H, m), 2.1 (4H, m), 3.7 (2H, m), 4.30 and 4.68(2H, ABq, J=13 Hz), 5.20 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz),8.3 (2H, broad s), 9.48 (1H, d, J=8 Hz),

(11)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 215° to 220° C. (dec.).

IR (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000,980, 740 cm⁻¹

NMR (DMSO-d₆, δ): 1.57 (6H, s), 3.70 (2H, m), 5.22 (1H, d, J=5 Hz), 5.97(1H, dd, J=5 and 8 Hz), 6.58 (1H, m), 8.25 (2H, broad s), 9.52 (1H, d,J=8 Hz)

(12)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 180° C.

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1520, 1260, 1100, 1040, 1000cm⁻¹

NMR (DMSO-d₆, δ): 1.46 (3H, d, J=8 Hz), 3.50 and 3.74 (2H, ABq, J=18Hz), 4.2 and 4.46 (2H, ABq, J=14 Hz), 4.72 (1H, q, J=8 Hz), 4.98 (2H,m), 5.12 (1H, d, J=5 Hz), 5.2-5.36 (2H, m), 5.76-6.1 (3H, m), 8.12 (2H,m), 9.48 and 9.56 (1H, d, J=8 Hz)

(13)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 212° to 217° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000,970, 730 cm⁻¹

NMR (DMSO-d₆, δ): 1.70 (4H, m), 2.30 (4H, m), 3.60 (2H, m), 5.10 (1H, d,J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 6.47 (1H, m), 8.20 (2H, m), 9.50(1H, d, J=8 Hz)

(14)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanicacid (syn isomer).

IR (Nujol): 3300, 3200, 1770, 1710, 1670, 1520, 1230, 1040 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (3H, d, J=8 Hz), 2.03 (3H, s), 3.58 (2H, m),4.13-5.00 (1H, m), 4.68 and 5.03 (2H, ABq, J=8 Hz), 5.26 (1H, d, J=5Hz), 5.87 (1H, dd, J=5 and 8 Hz), 8.15 (2H, broad s), 9.42 and 9.55 (1H,d, J=8 Hz)

(15)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-aminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 195° to 200° C. (dec.).

IR (Nujol): 3150, 1760, 1670, 1620, 1520, 1170, 990 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.50 (6H, s), 3.27 (2H, m), 3.60 (2H, m), 4.17(2H, m), 4.57 (2H, m), 5.10 (1H, d, J=5 Hz), 5.80 (1H, d, J=5 Hz)

EXAMPLE 50

Pivaloyl chloride (66 mg) was added to ambient temperature to a stirredsolution of7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-hydroxy-cephem-4-carboxylicacid (syn isomer) (115 mg) in tetrahydrofuran (1.5 ml). Sodium acetate(82 mg) was added thereto after 5 minutes and it was stirred for 10hours at ambient temperature. The reaction mixture was evaporated and tothe residue were added ethyl acetate and diluted aqueous solution ofsodium bicarbonate. To the aqueous layer was added ethyl acetate and themixture was adjusted to pH 1 to 2 with hydrochloric acid and extracted.The extract was washed with water and an aqueous solution of sodiumchloride, dried over magnesium sulfate and evaporated. The residue wastriturated with diethyl ether to give white powder of7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer) (70 mg), mp 170° to 175° C. (dec.).

IR (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635, 1625,1570, 1505 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.07 (8H, m), 3.43-3.77 (2H, m), 4.60-4.93 (1H,m), 5.15 (1H, d, J=5 Hz), 5.90 (1H, dd, J=5 and 8 Hz), 6.43-6.67 (1H,m), 8.23 (2H, broad s), 9.63 (1H, d, J=8 Hz)

EXAMPLE 51

The following compounds were obtained according to a similar manner tothat of Example 50.

(1)7-[2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 90° to 95° C. (dec.).

IR (Nujol): 3400, 3380, 3230, 1780, 1730, 1685, 1635, 1530 cm⁻¹

(2)7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3350, 3250, 3180, 1790, 1720, 1660, 1630, 1620, 1520 cm⁻¹

(3)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 215° C.

IR (Nujol): 3400, 3300, 3150, 1780, 1710, 1690, 1620, 1520, 1240, 1140,980 cm⁻¹

(4)7-[2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 250° C.

IR (Nujol): 3400, 3250, 3150, 1770, 1720, 1680, 1610, 1520, 1290, 1240,1150, 980, 740 cm⁻¹

(5)7-[2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 210° C.

IR (Nujol): 3450, 3300, 3200, 1760, 1660, 1560, 1290, 1210, 1000, 970,940, 730 cm⁻¹

(6)7-[2-(2,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 240° C.

IR (Nujol): 3250, 1770, 1660, 1620, 1540, 1520, 1280, 1230, 1100, 1050,970, 920, 810, 750 cm⁻¹

(7)7-[2-{1-Cyclohexyloxycarbonyl)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 163° C. (dec.).

IR (Nujol): 3420, 3300, 3180, 1775, 1720, 1685, 1610, 1520, 1290, 1230,1040, 980, 740 cm⁻¹

(8)7-[2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 165° to 169° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1710, 1680, 1610, 1520, 1290, 1240,1150, 1000, 970, 740 cm⁻¹

(9)7-[2-(α-Carboxybenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3400, 3280, 3160, 2600, 1770, 1720, 1670, 1625, 1520 cm⁻¹

(10)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 180° to 185° C. (dec.).

IR (Nujol): 3350, 3250, 1770, 1720, 1680, 1630, 1530 cm⁻¹

(11)7-[2-(1-Carboxy-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 215° to 220° C. (dec.).

IR (Nujol): 3400, 3250, 3200, 1770, 1670, 1520, 1290, 1240, 1160, 1000,980, 740 cm⁻¹

(12)7-[2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 230° to 235° C. (dec.).

IR (Nujol): 3400, 3250, 3150, 1760, 1720, 1660, 1610, 1550, 1290, 1240,1170, 970, 740 cm⁻¹

(13)7-[2-(1-Carboxy-1-cyclopentyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 212° to 217° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240, 1180, 1000,970, 730 cm⁻¹

(14)7-[2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3300, 3200, 1775, 1670, 1620, 1530 cm⁻¹

(15)7-[2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 177° to 180° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1730, 1680, 1610, 1520, 1240, 1160,1040, 980, 740 cm⁻¹

(16)7-[2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 147° to 151° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1680, 1610, 1520, 1280, 1235,1155, 1045, 980, 740 cm⁻¹

(17) 4-Nitrobenzyl7-[2-phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

I.R. (Nujol): 3300, 1775, 1720, 1680, 1625, 1600, 1590, 1520 cm⁻¹

(18) 4-Nitrobenzyl7-[2-(4-fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylic(syn isomer), mp 135° to 140° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1720, 1680, 1625, 1605, 1500, 1495 cm⁻¹

(19) 4-Nitrobenzyl7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.).

I.R. (Nujol): 3300, 3180, 1770, 1720, 1680, 1625, 1600, 1580, 1520, 1480cm⁻¹

(20) 4-Nitrobenzyl7-[2-(3-trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 136° to 140° C. (dec.).

I.R. (Nujol): 3370, 3200, 1780, 1730, 1690, 1680, 1630, 1610, 1520,1450, 1325, 1280, 1160, 1125, 975, 850, 740 cm⁻¹

(21)7-[2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), which is decomposed by 193° C.

I.R. (Nujol): 3450, 3320, 3200, 1770, 1710, 1665, 1630, 1560, 1515,1325, 1170, 1110, 940 cm⁻¹

(22)7-[2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 168° to 170° C. (dec.).

I.R. (Nujol): 3400, 3200, 1780, 1660, 1620, 1600, 1590, 1540 cm⁻¹

(23)7-[2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3400, 3260, 3180, 1775, 1675, 1625, 1600, 1520, 1480 cm⁻¹

(24)7-[2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec.).

I.R. (Nujol): 3400, 3270, 3180, 1765, 1675, 1605, 1500 cm⁻¹

(25) 4-Nitrobenzyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylate(syn isomer), mp 125° to 130° C. (dec.).

I.R. (Nujol): 3300, 1770, 1720, 1680, 1630, 1610, 1520 cm⁻¹

(26)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer), mp 160° to 165° C. (dec.).

(27)7-[2-(2-Cyclopenten-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). mp 180° to 185° C. (dec.).

I.R. (Nujol): 3500, 3430, 3300, 3200, 1770, 1690, 1660, 1640, 1620,1580, 1510 cm⁻¹

(28)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). mp 170° to 175° C.

I.R. (Nujol): 3520, 3420, 3320, 3220, 3160, 1770, 1685, 1655, 1635,1625, 1570, 1505 cm⁻¹

(29)7-[2-(2-Cyclohexen-1-yl)oxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). mp 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1630, 1520 cm⁻¹

(30)7-[2-Cycloheptyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-4-carboxylicacid (syn isomer). white powder. mp 170° to 175° C. (dec.).

I.R. (Nujol): 3400, 3300, 3200, 1770, 1670, 1620, 1520, 1280, 1240,1160, 1000, 980, 730 cm⁻¹

EXAMPLE 52

The following compounds were obtained according to a similar manner tothat of Example 30.

(1) 1-Acetoxyethyl7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3400, 3310, 3150, 1780, 1750, 1675 cm⁻¹

NMR (DMSO-d₆, δ): 1.2-1.6 (6H, m), 1.5-2.1 (8H, m), 2.07 (3H, s),3.6-4.1 (1H, m), 4.6-5.0 (1H, m), 5.17 (1H, d, J=4.5 Hz), 5.95 (1H, dd,J=4.5 and 8 Hz), 6.67 (1H, d, J=6 Hz), 6.90 (1H, q, J=5 Hz), 8.12 (2H,broad s), 9.45 (1H, d, J=8 Hz)

(2) 1-Isobutyryloxyethyl7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), amorphous powder.

IR (Nujol): 3400, 3300, 3170, 1780, 1745, 1675, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.08 (6H, d, J=7 Hz), 1.2-2.2 (14H, m), 2.2-2.9 (1H,m), 3.88 (1H, q, J=7 Hz), 4.6-5.0 (1H, m), 5.12 (1H, d, J=4.5 Hz), 5.90(1H, dd, J=4.5 and 8 Hz), 6.63 (1H, d, J=7 Hz), 8.06 (2H, broad s), 9.43(1H, d, J=8 Hz)

(3) 1-Acetoxypropyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 110° to 128° C. (dec.).

IR (Nujol): 3400, 3280, 3150, 1780, 1750, 1730, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 0.92 (3H, t, J=7.5 Hz), 1.42 (3H, d, J=7 Hz),1.8-2.5 (4H, m), 1.5-2.3 (2H, m), 2.05 (3H, s), 3.6-4.1 (1H, m), 5.10(1H, d, J=4.5 Hz), 5.1-5.5 (1H, m), 5.7-6.3 (3H, m), 6.4-6.9 (2H, m)

(4) 1-(2-Azidoethoxycarbonyloxy)ethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 85° to 100° C. (dec.).

IR (Nujol): 3310, 2200,1760-1785, 1680 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.48 (3H, d, J=6 Hz), 1.5 (3H, d, J=4.5 Hz),2.0-2.5 (4H, m), 3.5-4.1 (1H, m), 3.63 (2H, t, J=4 Hz), 4.30 (2H, t, J=4Hz), 5.16 (1H, d, J=4.5 Hz), 5.2-5.45 (1H, m), 5.7-6.2 (2H, m), 6-6.2(1H, m), 6.6-6.8 (1H, m), 6.7 (1H, d, J=6 Hz)

(5) 1-Ethoxycarbonyloxyethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3420, 3300, 3150, 1780, 1760 1675, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1 23 (3H, t, J=8 Hz), 1.42 (3H, d, J=7 Hz), 1.88(3H, d, J=5 Hz), 1.8-2.5 (4H, m), 3.6-4.1 (1H, m), 4.19 (2H, q, J=8 Hz),5.18 (1H, d, J=5 Hz), 5.2-5.6 (1H, m), 5.9-6.3 (2H, m), 5.95 (1H, d, J=5Hz), 6.8 (1H, d, J=7 Hz), 6.83 (1H, q, J=5 Hz)

(6) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), powder, mp 66° to 75° C. (dec.).

IR (Nujol): 3300, 1780, 1745, 1680, 1620 cm¹

(7) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1745, 1680, 1620 cm⁻¹

(8) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer).

IR (Nujol): 3300, 3150, 1783, 1745, 1675, 1615 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.15 (9H, s), 1.37 (9H, s), 1.5-2.0 (2H, m),2.65 (3H, s), 2.8-3.2 (2H, m), 3.5-3.8 (2H, m), 3.9-4.3 (2H, m), 4.16and 4.53 (2H, ABq, J=13 Hz),

5.17 (1H, d, J=4.5 Hz), 5.6-6.0 (3H, m)

(9) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 88° to 101° C. (dec.).

IR (Nujol): 3300, 1780, 1750, 1675, 1620 cm⁻¹

(10) Pivaloyloxymethyl7-[2-{3-(N-t-butoxycarbonylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), powder, mp 71° to 84° C. (dec.).

IR (Nujol): 3300, 1780, 1745, 1680, 1615 cm⁻¹

(11) Pivaloyloxymethyl7-[2-(2-cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanate(syn isomer), mp 93° to 101° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1780, 1740, 1675, 1615, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.13 (9H, s), 1.4-2.2 (6H, m), 2.02 (3H, s),3.58 (2H, s), 4.50-4.93 (1H, m), 4.68 and 4.90 (2H, ABq, J=13.5 Hz),5.18 (1H, d, J=4.5 Hz), 5.6-6.2 (5H, m)

(12) Phthalid-3-yl ester of7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 131° to 144° C. (dec.).

IR (Nujol): 3420, 3210, 3150, 1780, 1740, 1675, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.45 (3H, d, J=7 Hz), 1.9-2.5 (4H, m), 5.13 (1H,d, J=4.5 Hz), 5.2-5.5 (1H, m), 5.7-6.3 (3H, m), 6.75 (1/2H, d, J=6 Hz),6.77 (1/2H, d, J=6 Hz), 7.62 (1/2H, s), 7.65 (1/2H, s), 7.83 (4H, broads)

(13) Pivaloyloxymethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 111° to 124° C. (dec.).

IR (Nujol): 3400, 3300, 3270, 1775, 1740, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.17 (9H, s), 1.45 (3H, d, J=7 Hz), 1.9-2.4 (4H,m), 3.7-4.0 (1H, m), 5.1-5.6 (1H, m), 5.13 (1H, d, J=4.5 Hz), 5.7-6.3(5H, m), 6.65 (1H, d, J=7 Hz)

(14) 1-Benzoyloxyethyl7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp 132° to 137° C. (dec.).

IR (Nujol): 3400, 3300, 3160, 1780, 1738, 1680, 1620 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.43 (3H, d, J=7 Hz), 1.62 (3H, d, J=5 Hz),1.7-2.4 (4H, m), 3.84 (1H, q, J=7 Hz), 5.0-5.4 (1H, m), 5.13 (1H, d,J=4.5 Hz), 5.6-6.3 (3H, m), 6.70 (1H, d, J=6 Hz), 7.16 (1H, q, J=5 Hz),7.3-8.2 (5H, m)

(15) Pivaloyloxymethyl7-[2-{4-(N-t-butoxycarbonylamino)methylbenzyloxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-methyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 cm⁻¹

(16) Pivaloyloxymethyl7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-{2-(N-t-butoxycarbonylamino)ethyl)}-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate(syn isomer), powder.

IR (Nujol): 3300, 1780, 1750, 1680 cm⁻¹

EXAMPLE 53

A solution of 2-(1-amino-1-cyclohexyl)acetyl chloride hydrochloride(127.2 mg) in methylene chloride (2 ml) was dropwise added over 5minutes to a stirred solution of7-[2-(3-amino-propoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer) (132 mg) and bis(trimethylsilyl)acetamide (0.6 ml) inmethylene chloride (6 ml) at -30° C. and then the mixture was stirredfor 30 minutes at -30° to -35° C. The stirring was continued afteraddition of a saturated aqueous solution of sodium bicarbonate and thereaction mixture was post-treated in a conventional manner to give7-[2-{3-(N-(2-(1-amino-1-cyclohexyl)acetyl)amino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer) (85 mg), mp 198°-224° C. (dec.).

IR (Nujol): 3250, 3150, 1760, 1640, 1580, 1520 cm⁻¹

NMR (D₂ O+DCl, δ): 1.0-2.2 (15H, m), 2.65 (2H, s), 3.1-3.6 (2H, m),3.6-4.1 (1H, m), 4.1-4.6 (2H, m), 5.0-5.3 (1H, m), 5.95 (1H, d, J=4.5Hz), 6.82 (1H, d, J=6 Hz)

EXAMPLE 54

The following compounds were obtained according to a similar manner tothat of Example 53.

(1)7-[2-{2-(N-(N-t-Butoxycarbonyl)-D-phenylglycylamino)ethoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 77° to 91° C. (dec.).

IR (Nujol): 3300, 3160, 1775, 1680, 1660, 1630, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.40 (3H, d, J=8 Hz), 3.1-4.2 (5H, m),5.08 (1H, d, J=4.5 Hz), 5.10 (1H, d, J=8 Hz), 5.90 (1H, dd, J=4.5 and 9Hz), 6.53 (1H, d, J=7.5 Hz), 7.32 (5H, s), 8.13 (2H, broad s), 9.48 (1H,d, J=9 Hz)

(2)7-[2-{3-(N-(N-t-Butoxycarbonyl)-D-phenylglycylamino)propoxyimino}-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3300, 3200, 1775, 1700, 1650, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.3-1.6 (12H, m), 1.6-2.0 (2H, m), 2.8-3.4 (2H,m), 3.82 (1H, q, J=7.5 Hz), 3.9-4.3 (2H, m), 5.05 (1H, d, J=4.5 Hz),5.83 (1H, d, J=4.5 Hz), 6.48 (1H, d, J=6 Hz)

PREPARATION 23

Potassium iodate (20.0 g) was added at ambient temperature to a stirredsolution of iodine (7.7 g) in conc. sulfuric acid (70 ml), and themixture was stirred for 1.5 hours at 35° to 40° C. Acetic anhydride (30ml) was added thereto under 10° C. over 0.5 hour and then1,2-dichlorobenzene (44.69 g) was added thereto under 10° C. over 0.5hour. The mixture was stirred for 1 hour at the same temperature andthen stirred for 19 hours at ambient temperature. The reaction mixturewas poured into ice-water (500 ml) and washed with diethyl ether. To theaqueous layer was added an aqueous solution (50 ml) of sodium chloride(8.9 g) and precipitates were collected by filtration and washed withice-water to give 3,4,3',4'-tetrachlorodiphenyliodonium chloride (58 g),mp 183° to 186° C. (dec.).

IR (Nujol): 1555, 1450, 1250, 1210, 1170, 1125, 1030 cm⁻¹

PREPARATION 24

The following compounds were obtained according to a similar manner tothat of Preparation 23.

(1) 3,3'-Di(trifluoromethyl)diphenyliodonium chloride.

IR (Nujol): 3600-3200, 1600, 1420, 1320, 1310, 1190, 1170, 1120, 1095,1085, 1055, 800, 700, 685 cm⁻¹

(2) 3,3'-Dicarboxydiphenyliodonium bromide

IR (Nujol): 3400, 1700, 1290, 1250, 1210, 1170, 1050, 750 cm⁻¹

(3) 3,3'-Di(ethoxycarbonyl)diphenyliodonium bromide, mp 154° to 157° C.

IR (Nujol): 1730, 1295, 1280, 1255, 1110, 1020, 750 cm⁻¹

PREPARATION 25

The following compounds were obtained according to similar manners tothose of Preparations 1-(1) and 1-(2).

(1) N-(3-Phthalimidopropoxy)phthalimide, mp 168° to 170° C.

IR (Nujol): 1790, 1770, 1730, 1710, 1390, 1060, 725, 705 cm⁻¹

(2) N-(1-Cyclohexyloxycarbonylethoxy)phthalimide, mp 50° to 54° C.

NMR (d₆ -DMSO, δ): 1.51 (3H, d, J=7 Hz), 0.9-2.1 (10H, m), 4.7 (1H, m),4.82 (1H, 9, J=7 Hz), 7.87 (4H, s)

(3) N-(α-t-Butoxycarbonylbenzyloxy)phthalimide.

(4) N-(1-t-Butoxycarbonyl-2-methylpropoxy)phthalimide, mp 84° to 87° C.

IR (Nujol): 1790, 1730, 1360, 1160, 1140, 1000, 880, 780, 700 cm⁻¹

(5) N-(1-t-Butoxycarbonylpropoxy)phthalimide, mp 49° to 52° C.

NMR (d₆ -DMSO, δ): 1.02 (3H, t, J=7 Hz), 1.40 (9H, s), 1.9 (2H, m), 4.55(1H, t, J=6 Hz), 7.82 (4H, s)

(6) N-(1-t-Butoxycarbonylethoxy)phthalimide, mp 80° to 82° C.

NMR (d₆ -DMSO, δ): 1.42 (9H, s), 1.48 (3H, d, J=7 Hz), 4.72 (1H, q, J=7Hz), 7.86 (4H, s)

(7) N-(1-t-Butoxycarbonyl-1-methylethoxy)phthalimide, mp 96° to 100° C.

NMR (d₆ -DMSO, δ): 1.42 (9H, s), 1.48 (6H, s), 7.87 (4H, s)

(8) N-(1-Butoxycarbonylethoxy)phthalimide, mp 48° to 53° C.

IR (Nujol): 1755, 1720, 1210, 1140, 1110, 1080, 875, 695 cm⁻¹

(9) N-(1-Benzyloxycarbonylethoxy)phthalimide, mp 65° to 68° C.

IR (Nujol): 1790, 1740, 1450, 1210, 1190, 1110, 1080, 980, 880, 735, 700cm⁻¹

(10) N-(2-Oxo-3-tetrahydrofuryloxy)phthalimide, mp 140° to 142° C.

IR (Nujol): 1785, 1760, 1720, 1605, 1215, 1185, 870, 695 cm⁻¹

PREPARATION 26

The following compounds were obtained according to a similar manner tothat of Preparation 2.

(1) 3-Aminopropoxyamine dihydrochloride

NMR (D₂ O, δ): 2.20 (2H, m), 3.27 (2H, t, J=7 Hz), 4.33 (2H, t, J=6 Hz)

(2) 1-Phenylethoxyamine

(3) 1-t-Butoxycarbonyl-2-methylpropoxyamine

(4) α-t-Butoxycarbonylbenzyloxyamine

(5) 1-Butoxycarbonylethoxyamine

PREPARATION 27

The following compounds were obtained according to a similar manner tothat of Preparation 17.

(1)2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3420, 3230, 3100, 1725, 1610, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (9H, s), 4.70 (2H, s), 8.12 (2H, broad s)

(2)2-(1-Cyclohexyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 175° to 180° C. (dec.).

IR (Nujol): 3380, 3260, 3170, 1720, 1610, 1520, 1220, 990, 710 cm⁻¹

NMR (d₆ -DMSO, δ): 0.9-2.1 (13H, m), 4.7 (1H, m), 4.85 (1H, q, J=6 Hz),8.13 (2H, broad s)

(3)2-(Thiolan-1,1-dioxide-3-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 200° to 205° C. (dec.).

IR (Nujol): 3300, 1720, 1620, 1530 cm⁻¹

NMR (d₆ -DMSO, δ): 2.20-2.50 (2H, m), 3.00-3.50 (4H, m), 5.00-5.27 (1H,m), 8.20 (2H, s)

(4)2-(α-t-Butoxycarbonylbenzyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 155° to 160° C. (dec.).

IR (Nujol): 3440, 3350, 3250, 1750, 1730, 1640, 1535 cm⁻¹

NMR (d₆ -DMSO, δ): 1.37 (9H, s), 5.67 (1H, s), 7.45 (5H, s), 8.25 (2H,broad s)

(5)2-(1-t-Butoxycarbonyl-2-methylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 158° to 162° C. (dec.).

IR (Nujol): 3600, 3400, 1740, 1720, 1630 cm⁻¹

NMR (d₆ -DMSO, δ): 0.95 (6H, d, J=7 Hz), 1.8-2.4 (1H, m), 4.33 (1H, d,J=6 Hz), 8.13 (2H, broad s)

(6)2-(1-t-Butoxycarbonylpropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 152° to 155° C. (dec.).

NMR (d₆ -DMSO, δ): 0.94 (3H, t, J=7 Hz), 1.42 (9H, s), 1.80 (2H, m),4.51 (1H, t, J=6 Hz), 8.16 (2H, broad s)

(7)2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 155° to 156° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1720, 1710, 1620, 1520 cm⁻¹

NMR (d₆ -DMSO, δ): 1.2-1.7 (12H, m), 4.72 (1H, q, J=7 Hz), 8.2 (2H,broad s)

(8)2-(1-t-Butoxycarbonyl-1-methylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 180° to 181° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1745, 1715, 1630, 1530 cm⁻¹

NMR (d₆ -DMSO, δ): 1.38 (9H, s), 1.43 (6H, s), 815 (2H, broad s)

(9)2-(1-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 120° to 123° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1725, 1615, 1510, 1410, 1210, 1170, 1135,1100, 1040, 990, 870, 720 cm⁻¹

NMR (DMSO-d₆, δ): 0.85 (3H, t, J=6 Hz), 1.43 (3H, d, J=7 Hz), 1.0-1.7(4H, m), 4.12 (2H, t, J=6 Hz), 4.85 (1H, q, J=7 Hz), 8.04 (2H, broad s)

(10)2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 129° to 133° C. (dec.).

IR (Nujol): 3300, 3200, 1720, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (3H, d, J=6 Hz), 4.97 (1H, q, J=6 Hz), 5.18 (2H,s), 7.31 (5H, s), 8.17 (2H, broad s)

PREPARATION 28

The following compounds were obtained according to a similar manner tothat of Preparation 15.

(1)2-(Thiolan-1,1-dioxide-3-yloxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 214° C. (dec.).

IR (Nujol): 3200, 1720, 1680, 1600, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 2.30-2.50 (2H, m), 2.90-3.83 (4H, m), 5.10-5.50 (1H,m), 8.92 (1H, s)

(2) 2-(1-Phenylethoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 174° to 175° C. (dec.).

IR (Nujol): 3100, 1720, 1690, 1550 cm⁻¹

NMR (d₆ -DMSO, δ): 1.58 (3H, d, J=6 Hz), 5.44 (1H, q, J=6 Hz), 7.32 (5H,m), 8.78 (1H, m), 13.34 (1H, broad s)

PREPARATION 29

To the aqueous solution containing sodium2-(3-aminopropoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetate(syn isomer), which was prepared by a similar manner to that ofPreparation 15, were added triethylamine (20 g) and a solution of2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (27 g) in dioxane (270ml) and the mixture was stirred at ambient temperature for 2 hours.After evaporation of dioxane, the aqueous solution was adjusted to pH 6with 10% hydrochloric acid and washed with ethyl acetate. To the aqueouslayer was added ethyl acetate and the mixture was adjusted to pH 3 with10% hydrochloric acid. The organic layer was washed with brine, driedover magnesium sulfate and evaporated to dryness. The residue wastriturated with diisopropyl ether to give2-[3-(N-t-butoxycarbonylamino)propoxyimino]-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (14.2 g), mp 115°-117° C. (dec.).

IR (Nujol): 3320, 3150, 1740, 1680, 1560-1530, 1400, 1230, 1140, 1040,1030, 890 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (9H, s), 1.97 (2H, m), 3.10 (2H, t, J=7 Hz), 4.30(2H, t, J=7 Hz), 8.80 (1H, s)

PREPARATION 30

The following compounds were obtained according to similar manners tothose of Preparations 13 and 29.

(1)2-[2-(N-t-Butoxycarbonylamino)ethoxyimino]-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 139° to 154° C. (dec.).

IR (Nujol): 3400, 3150, 1748, 1700, 1690, 1540 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.45 (9H, s), 3.40 (2H, t, J=6 Hz), 4.32 (2H, t,J=6 Hz), 8.07 (1H, s)

(2)2-[4-(N-t-Butoxycarbonylaminomethyl)benzyloxyimino]-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

IR (Nujol): 3300, 3150, 1700 cm⁻¹

NMR (DMSO-d₆, δ): 1.65 (9H, s), 4.12 (2H, d, J=5.5 Hz), 5.19 (2H, s),7.21 (4H, s)

PREPARATION 31

The following compounds were obtained according to a similar manner tothat of Preparation 4.

(1)2-[2-(N-t-Butoxycarbonylamino)ethoxyimino]-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 172°-177° C. (dec.).

IR (Nujol): 3300, 3140, 1738, 1680, 1628, 1595, 1550, 1527, 1285, 1245,1165, 1120 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.42 (9H, s), 3.35 (2H, t, J=6 Hz), 4.22 (2H, t,J=6 Hz)

(2)2-[3-(N-t-Butoxycarbonylamino)propoxyimino]-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

IR (Nujol): 3300, 3150, 2600-2400, 1720-1660, 1620, 1530, 1250, 1160,1030, 720 cm⁻¹

NMR (DMSO-d₆, δ): 1.33 (9H, s), 1.82 (2H, m), 3.03 (2H, m), 4.17 (2H, t,J=6 Hz), 6.73 (1H, broad s), 8.13 (2H, broad s)

(3) 2-(4-Chlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 150°-155° C. (dec.).

IR (Nujol): 3300, 3200, 1710, 1640, 1580, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 7.37 (2H, d, J=9 Hz), 7.67 (2H, d, J=9 Hz), 8.50 (2H,broad s)

(4) 2-(4-Fluorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 140°-145° C. (dec.).

IR (Nujol): 3450, 3300, 3200, 1730, 1630, 1530, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 7.17 (2H, s), 7.27 (2H, s), 8.27 (2H, s)

(5)2-[1-t-Butoxycarbonyl-1-cyclopentyloxyimino]-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 174°-175° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1745, 1715, 1630, 1530 cm⁻¹

NMR (d₆ -DMSO, δ): 1.37 (9H, s), 1.65 (4H, m), 1.97 (4H, m), 8.17 (2H,broad s)

(6) 2-(1-Phenylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid(syn isomer), mp 103°-107° C. (dec.).

IR (Nujol): 3250, 3150, 1710, 1610, 1520 cm⁻¹

NMR (d₆ -DMSO, δ): 1.57 (3H, d, J=6 Hz), 5.42 (1H, q, J=6 Hz), 7.40 (5H,m), 8.20 (2H, m)

PREPARATION 32

To a solution of2-hydroxyimino-2-(5-formamido-1,2,4-thiadiazol-3-yl)acetic acid (synisomer) (7.2 g) in an aqueous methanolic sodium hydroxide prepared frommethanol (83.7 ml) and 1 N aqueous solution of sodium hydroxide (83.7ml) was added 4,4'-difluorodiphenyliodonium chloride (11.8 g) and themixture was stirred at ambient temperature for an hour. The resultingoily substance was removed by decantation and the solution wasconcentrated under reduced pressure to remove methanol. The aqueoussolution was acidified with 10% hydrochloric acid and extracted withethyl acetate. The extract was washed with water, dried over magnesiumsulfate and evaporated to dryness. The residue was triturated withdiisopropyl ether to give2-(4-fluorophenoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (6.0 g), mp 130°-135° C. (dec.).

IR (Nujol): 3100, 3050, 1730, 1690, 1530, 1500 cm⁻¹

NMR (DMSO-d₆, δ): 7.17 (2H, s), 7.27 (2H, s), 8.83 (1H, s), 13.43 (1H,s)

PREPARATION 33

The following compounds were obtained by a similar manner to that ofPreparation 32.

(1) 2-(4-Chlorophenoxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn iosmer), mp 155° to 160° C. (dec.).

IR (Nujol): 3180, 1725, 1690, 1580, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 7.30 (2H, d, J=9 Hz), 7.57 (2H, d, J=9 Hz), 9.0 (1H,s)

(2)2-(2-Methoxy-5-nitrophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 125° to 128° C. (dec.).

IR (Nujol): 3400, 3280, 1740, 1720, 1690, 1630, 1590, 1510, 1340, 1275,970, 720 cm⁻¹

NMR (DMSO-d₆, δ): 3.93 (3H, s), 7.27 (1H, d, J=8 Hz), 8.01 (1H, d, J=8Hz), 8.07 (1H, s), 8.30 (2H, broad s)

PREPARATION 34

The following compound was obtained by a similar manner to that ofPreparation 21.

2-(1-t-Butoxycarbonyl-1-cyclopentyloxyimino)-2-(5-formamido-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 140° to 141° C. (dec.).

IR (Nujol): 3550, 1730, 1670, 1550, 1540, 1280, 1255, 1150, 980, 720cm⁻¹

NMR (DMSO-d₆, δ): 1.48 (9H, s), 1.83 (4H, m), 2.03 (4H, m), 8.87 (1H,s), 13.6 (1H, broad s)

PREPARATION 35

The following compounds were obtained according to a similar manner tothat of Preparation 32 by using2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer)as a starting compound, which was prepared by a similar manner to thatof Preparation 4.

(1) 2-(O-and P-Tolyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer).

NMR (d₆ -DMSO, δ): 2.20 (1H, s), 2.27 (2H, s), 6.97-7.43 (4H, m), 8.33(2H, bs)

(2) 2-(3,4-Dichlorophenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 177° to 178° C.

IR (Nujol): 3300, 1710, 1625, 1585, 1530, 1300, 1210, 1120, 980 cm⁻¹

NMR (DMSO-d₆, δ): 6.83-7.73 (3H, m), 8.38 (2H, broad s)

(3)2-(3-Trifluoromethylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 167° to 168° C. (dec.).

IR (Nujol): 3250, 1645, 1620, 1590, 1450, 1320, 1170, 1140, 1010, 995,845, 730 cm⁻¹

NMR (DMSO-d₆, δ): 7.63 (4H, m), 8.44 (2H, broad s)

(4)2-(3-Ethoxycarbonylphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 161° to 164° C. (dec.).

IR (Nujol): 3400, 3300, 3180, 1755, 1720, 1690, 1630, 1590, 1545, 1410,1290, 1275, 970, 900, 755 cm⁻¹

NMR (DMSO-d₆, δ): 1.36 (3H, t, J=7 Hz), 4.40 (12H, q, J=7 Hz), 7.4-8.0(3H, m), 8.5 (2H, broad s)

(5) 2-(3-Carboxyphenoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp 186° to 188° C. (dec.).

IR (Nujol): 3420, 3150, 1735, 1690, 1620, 1580, 1265, 1200, 1000, 980,760 cm⁻¹

NMR (DMSO-d₆, δ): 7.3-8.0 (4H, m), 8.30 (2H, broad s)

(6) 2-Phenoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (synisomer), mp 145° to 147° C. (dec.).

IR (Nujol): 3350, 3170, 2500, 1730, 1710, 1645, 1630, 1595, 1535 cm⁻¹

NMR (DMSO-d₆, δ): 7.0-7.5 (5H, m), 8.30 (2H, broad s)

PREPARATION 36

S-Methyl (5-formamido-1,2,4-thiadiazol-3-yl)thioglyoxylate (64.8 g) and1-carboxy-3-hydroxypropoxyamine, which was prepared by refluxing amixture of N-(2-oxo-3-tetrahydrofuryloxy)phthalimide (65.0 g), conc.hydrochloric acid (50 ml) and water (200 ml) for 1 hour, were treatedaccording to a similar manner to that of Preparation 17 to give2-(1-carboxy-3-hydroxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (33.2 g), mp 186° to 188° C. (dec.).

IR (Nujol): 3400, 3250, 3100, 1710, 1620, 1540 cm⁻¹

NMR (DMSO-d₆, δ): 1.73-2.10 (2H, m), 3.50 (2H, t, J=6 Hz), 4.73 (1H, t,J=6 Hz), 8.13 (2H, s)

PREPARATION 37

To a solution of 2-(1-carboxy-3-hydroxypropoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (33.0 g) in methanol (2.8 l) were added anhydrousmagnesium sulfate (120 g) and acetic anhydride (60 g). The mixture wasstirred at ambient temperature for 30 minutes, filtered and the filtratewas evaporated to dryness. The residue was triturated in acetone (200ml) and ethyl acetate (1 l) was added thereto. The mixture was stirredat ambient temperature for 1 hour and the precipitates were collected byfiltration and washed with ethyl acetate.

The precipitates were dissolved in water (200 ml) and then ethyl acetate(500 ml), acetone (200 ml) and 6 N hydrochloric acid (40 ml) were addedthereto.

An organic layer was separated out and the aqueous layer was extractedwith ethyl acetate. The organic layers were combined, dried overanhydrous magnesium sulfate and evaporated to dryness. The residue wastriturated in diethyl ether, filtered and washed with diisopropyl etherto give2-(2-oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (26.5 g), mp 185°-187° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1775, 1730, 1640, 1605, 1535 cm⁻¹

NMR (d₆ -DMSO, δ): 2.27-2.70 (2H, m), 4.17-4.50 (2H, m), 5.27 (1H, t,J=8 Hz), 8.22 (2H, s)

PREPARATION 38

(1) The following compound was obtained by a similar manner to that ofPreparation 22-(1).

Methyl N-(6-acetamidohexyl)dithiocarbamate

NMR (DMSO-d₆, δ): 1.33 (8H, broad s), 1.80 (3H, s), 2.50 (3H, s), 3.07(2H, m), 3.53 (2H, m), 7.77 (1H, m), 9.80 (1H, m)

(2) The following compounds were obtained by a similar manner to that ofPreparation 22-(2).

(a) 1-(4-Acetamidobutyl)-1H-tetrazole-5-thiol

IR (Nujol): 3300, 1620, 1560, 1520 cm⁻¹

NMR (d₆ -DMSO, δ): 1.23-1.93 (4H, m), 1.77 (3H, s), 3.10 (2H, m), 4.23(2H, m), 7.80 (1H, broad s)

(b) 1-(6-Acetamidohexyl)-1H-tetrazole-5-thiol, oil.

(3) The following compounds were obtained by a similar manner to that ofPreparation 22-(3).

(a) 1-(4-Aminobutyl)-1H-tetrazole-5-thiol hydrochloride, white powder.

(b) 1-(6-Aminohexyl)-1H-tetrazole-5-thiol hydrochloride, red oil.

(4) The following compounds were obtained by a similar manner to that ofPreparation 22-(4).

(a) 1-[4-(N-t-Butoxycarbonylamino)butyl]-1H-tetrazole-5-thiol, mp107°-108.5° C.

IR (Nujol): 3200, 1640, 1520 cm⁻¹

NMR (d₆ -DMSO, δ): 1.37 (9H, s), 1.38-2.1 (4H, m), 2.97 (2H, m), 4.23(2H, m), 6.73 (1H, broad s)

(b) 1-[6-(N-t-Butoxycarbonylamino)hexyl]-1H-tetrazole-5-thiol, oil

NMR (d₆ -DMSO, δ): 1.40 (15H, m), 1.77 (2H, m), 2.93 (2H, m), 4.20 (2H,m), 6.70 (1H, broad s)

PREPARATION 39

(1) To the solution of N-(3-bromoporpyl)phthalimide (402 g) in acetone(2.5 l) were added 1-methylpiperazine (225 g) and potassium carbonate(4.15 g). The resulting mixture was refluxed with stirring for 3.5hours. The reaction mixture was cooled and then filtered. The filtercake was washed with acetone (500 ml). The filtrate and washing werecombined and evaporated under reduced pressure. The remaining startingmaterials in the residual oil were azeotropically removed with benzeneto give an oil of N-[3-(4-methyl-1-piperazinyl)propyl]phthalimide (502g). I.R. (Film): 1770, 1700 cm⁻¹

(2) To a solution of N-[3-(4-methyl-1-piperazinyl)propyl]phthalimide(502 g) in ethanol (3.0 l) was added 100% hydrazine hydrate (187.6 g).The resulting mixture was refluxed with stiving for 1.5 hours. Thereaction mixture was cooled and then filtered. The filter cake waswashed with ethanol (1 l). The filtrate and washing were combined andevaporated, under reduced pressure. The residual oil was distilled underreduced pressure to give 3-(4-methyl-1-piperazinyl)propylamine (146.6g), bp 34 mmHg/127° to 128° C.

(3) To a solution of potassium hydroxide (57.3 g) in methanol (250 ml)was added 3-(4-methyl-1-piperazinyl)propylamine (146 g) and thereto wasadded carbon disulfide (70.6 g) with stirring under ice cooling over aperiod of 40 minutes. The resulting mixture was stirred for 3.5 hoursunder ice cooling. The reaction mixture was evaporated under reducedpressure. The residual oil was dissolved in water (400 ml) and washedwith diethyl ether twice. The washed aqueous layer was ice-cooled andthereto was added methyl iodide (132.1 g) with stirring. The resultingmixture was stirred for 2 hours under ice-cooling, and extracted withethyl acetate (400 ml×3) and chloroform (400 ml×2). The extracts werecombined, dried over magnesium sulfate and then evaporated under reducedpressure to give methylN-[3-(4-methyl-1-peperazinyl)propyl]dithiocarbamate (139.3 g).

Thus obtained product was used directly in the next step reactionwithout further purification.

(4) To a solution of methylN-[3-(4-methyl-1-piperazinyl)propyl]dithiocarbamate obtained inPreparation 39 (3) (139.3 g) in a mixture of water (420 ml) and ethanol(280 ml) was added sodium azide (47.6 g). The resulting mixture wasrefluxed with stirring for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The concentrate was washedsuccessively with ethyl acetate and diethyl ether and then evaporated.To the residue was added ethanol and the mixture was filtered. Thefiltrate was evaporated under reduced pressure, and to the residual oilwas added 6 N hydrochloric acid. The mixture was evaporated underreduced pressure. The residue was recrystallized from isopropyl alcoholcontaining water to give1-[3-(4-methyl-1-piperazinyl)propyl]-1H-tetrazole-5-thioldihydrochloride (48.1 g), mp 239° to 243° C.

N.M.R. (D₂ O, δ): 2.3-2.8 (2H, m), 3.07 (3H, s) 3.3-3.7 (2H, m), 3.75(8H, s), 4.42 (2H, t, J=6 Hz).

EXAMPLE 55

The following compound was obtained according to a similar manner tothat of Example 40, 42 or 47.7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 215° to 220° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1720, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.93 (2H, t, J=6 Hz), 3.67 (2H, broad s), 4.33 (2H,broad s), 4.43 (2H, t, J=6 Hz), 4.67 (2H, s), 5.10 (1H, d, J=4 Hz), 5.83(1H, dd, J=4 and 8 Hz), 8.13 (2H, s), 9.50 (1H, d, J=8 Hz)

EXAMPLE 56

The following compounds were obtained according to a similar manner tothat of Example 30, 40, 42, 44, 45, 47 or 48.

(1)7-(2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-(1-(3-(N-t-butoxycarbonylamino)propyl)-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 130° to 135° C. (dec).

IR (Nujol): 3300, 3200, 1780, 1680, 1620, 1525 cm⁻¹

(2)7-(2-(2-Oxo-3-tetrahydrofuryloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-(1-(3-aminopropyl)-1H-tetrazol-5yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 210° to 215° C. (dec).

IR (Nujol): 3300, 3200, 1770, 1670, 1620, 1525 cm⁻¹

(3)7-(2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)cephalosporanicacid (syn isomer) mp 210° to 220° C. (dec).

IR (Nujol): 3400, 3300, 3200, 1770, 1720, 1700-1670, 1620, 1520, 1230,1150, 1060, 1020, 995, 975, 920, 740, 720 cm⁻¹

(4) Pivaloyloxymethyl7-(2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-2-methyl-3-cephem-4-carboxylate(syn isomer), amorphous powder.

IR (Nujol): 3450, 3360, 3200, 1790, 1750, 1680, 1625, 1530 cm⁻¹

(5)7-(2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido-3-(1-(3-aminopropyl)-1H-tetra-zol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 198° to 203° C. (dec).

IR (Nujol): 3450-3300, 3200, 1770, 1680, 1600-1615, 1525, 1140, 990,970, 750, 720 cm⁻¹

(6)7-(2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-(5-(2-(N-t-butoxycarbonyamino)ethyl)-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 202° to 204° C. (dec).

IR (Nujol): 3350, 3200, 1780, 1680, 1620, 1520, 1250, 1170, 1100, 1050,1000 cm⁻¹

(7)7-(2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-(5-(2-aminoethyl)-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 200° to 204° C. (dec).

IR (Nujol): 3350, 3200, 1770, 1680, 1620, 1520, 1240, 1180, 1100, 1060,1040, 1000 cm⁻¹

(8)N-(7-(2-(2-Cyclopenten-1-yl-oxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmethyl)-4'-carbamoyl-pyridinium-4-carboxylate(syn isomer), mp 155° to 160° C. (dec.)

IR (Nujol): 3300, 3150, 1770, 1675, 1610, 1560, 1520 cm⁻¹

(9)N-(7-(2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido)-3-cephem-3-ylmethyl)-4'-carbamoyl-pyridinium-4-carboxylate(syn isomer), mp 180° to 185° C. (dec.)

IR (Nujol): 3300, 1770, 1680, 1620, 1560, 1520 cm⁻¹

EXAMPLE 57

To a cold solution of phosphorus pentachloride (1.25 g) in methylenechloride (30 ml) was added2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl) aceticacid (syn isomer) (1.5 g) at -15° C. and the mixture was stirred for 30minutes at -13° to -10° C. On the other hand, a mixture ofN-[7-amino-3-cephem-5-ylmethyl]pyridinium-4-carboxylate dihydrochloride(1.82 g) and trimethylsilylacetamide (10 g) in methylene chloride (50ml) was stirred for 10 minutes at room temperature and cooled to -10° C.The cooled solution was added to the above activated mixture and themixture was stirred for 15 minutes at -10° C. The reaction mixture waspoured into an aqueous solution (100 ml) of sodium bicarbonate (3.6 g)and stirred for 15 minutes at room temperature. The aqueous layer wasseparated out, adjusted to pH 2 with 10% hydrochloric acid and washedwith ethyl acetate. The aqueous solution was subjected to columnchromatography on a non ionic adsorption resin, Diaion HP-20 (Trademark,prepared by Mitsubishi Chemical Industries) (100 ml). After the columnwas washed with water, the elution was carried out with 40% aqueousmethanol. The eluates containing an object compound were collected,evaporated to remove methanol under reduced pressure and lyophilized togive white powder ofN-[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer) (1.5 g), mp 190° to 195° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1660, 1620, 1530 cm⁻¹

N.M.R. (D₂ O+NaHCO₃, δ): 1.9-2.5 (4H, m), 3.23, 3.60 (2H, ABq, J=16 Hz),5.2-6.1 (7H, m), 7.9-9.1 (5H, m)

EXAMPLE 58

The following compounds were obtained according to similar manners tothose of Examples 1 to 3, 5, 7 to 12, 32 to 34, 40 and 57.

(1)N-[7-{2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 cm⁻¹

(2)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1530 cm⁻¹

(3)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm⁻¹

(4)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm⁻¹

(5)N-[7-{2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3290, 3160, 1770, 1725, 1670, 1620, 1525 cm⁻¹

N.M.R. (CD₃ OD+D₂ O, δ): 1.2-1.6 (12H, m), 3.20 and 3.67 (2H, ABq, J=18Hz), 4.40-4.90 (1H, m), 5.20 (1H, d, J=5 Hz), 5.33-5.80 (2H, m), 5.92(1H, d, J=5 Hz), 7.9-9.4 (5H, m).

(6)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620,1520 cm⁻¹

(7)N-[7-{2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 178° to 182° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1670, 1620,1520 cm⁻¹

N.M.R. (DMSO-d₆ +D₂ O, δ): 1.45 (3H, d, J=7 Hz), 3.10 and 3.60 (2H, ABq,J=16 Hz), 4.87 (1H, q, J=7 Hz), 5.20 (2H, s), 4.97-5.10 (2H, m), 5.25(1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz), 7.43 (5H, s), 8.27 (2H, m), 8.63(1H, m), 9.38 (2H, m)

(8)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1670, 1620,1520 cm⁻¹

(9)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3220, 1775, 1680, 1620, 1525 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.90-2.50 (4H, m), 2.70 (3H, s), 3.68 (2H, broads), 4.25 and 4.53 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz), 5.23-5.53(1H, m), 5.70-6.30 (3H, m), 8.15 (2H, broad s), 9.52 (1H, d, J=8 Hz)

(10)7-[2-(Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620,1530 cm⁻¹

(11)N-[7-{2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 184° to 188° C. (dec.).

I.R. (Nujol): 3400-3100, 1770, 1670, 1610, 1520 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.17 (3H, t, J=7 Hz), 3.05 and 3.53 (2H, ABq, J=18Hz), 4.13 (2H, q, J=7 Hz), 4.70 (2H, s), 5.08 (1H, d, J=5 Hz), 5.17 and5.70 (2H, ABq, J=13 Hz), 5.72 (1H, dd, J=5 and 8 Hz), 8.16 (4H, m), 8.62(1H, m), 9.50 (3H, m)

(12)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 145° to 150° C. (dec.).

I.R. (Nujol): 3350, 3220, 1775, 1670, 1620, 1525 cm⁻¹

(13)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1675, 1620,1525 cm⁻¹

(14)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1620,1520 cm⁻¹

EXAMPLE 59

The following compounds were obtained according to similar manners tothose of Examples 14 to 17 and 42.

(1)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 190° to 195° C. (dec.).

I.R. (Nujol): 3350,3200,1780,1660,1620,1530 cm⁻¹

(2)N-[7-{2-(t-Butoxycarbonylmethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1680, 1620, 1530 cm⁻¹

(3)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1530 cm⁻¹

(4)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 180° to 185° C. (dec.).

I.R. (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.4-2.0 (8H, m), 3.17, 3.53 (2H, ABq, J=18 Hz),4.60-4.83 (1H, m), 5.10 (1H, d, J=4 Hz), 5.30 and 5.83 (2H, ABq, J=14Hz), 5.87 (1H, dd, J=4 and 8 Hz), 8.17 (2H, s), 9.50 (1H, d, J=8 Hz),8.0-9.7 (5H, m)

(5)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.38 (3H, d, J=7 Hz), 3.10-3.60 (2H, m), 4.40-4.83(1H, m), 5.10 (1H, d, J=5 Hz), 5.28-6.00 (3H, m), 8.22 (2H, broad s),8.48 (2H, d, J=6 Hz), 9.48 (2H, d, J=6 Hz), 9.32-9.65 (1H, m)

(6)N-[7-{2-(1-t-Butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 160° to 165° C. (dec.).

I.R. (Nujol): 3290, 3160, 1770, 1725, 1670, 1620, 1525 cm⁻¹

(7)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm⁻¹

(8)N-[7-{2-(1-Benzyloxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 178° to 182° C. (dec.).

I.R. (Nujol): 3250, 3150, 1770, 1670, 1620, 1520 cm⁻¹

(9)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3190, 1770, 1670, 1620, 1520 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.27-2.07 (8H, m), 2.67 (3H, s), 3.68 (2H, broads), 4.23 and 4.53 (2H, ABq, J=13 Hz), 4.60-4.93 (1H, m), 5.13 (1H, d,J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 8.10 (2H, broad s), 9.47 (1H, d,J=8 Hz)

(10)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3220, 1775, 1680, 1620, 1525 cm⁻¹

(11)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3300, 3200, 1770, 1670, 1620, 1530 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.5-2.0 (8H, m), 3.62 and 3.72 (2H, ABq, J=17 Hz),4.20 and 4.42 (2H, ABq, J=14 Hz), 4.65-4.84 (1H, m), 5.15 (1H, d, J=4Hz), 5.80 (1H, dd, J=4 and 8 Hz), 8.10 (2H, s), 9.50 (1H, d, J=8 Hz)

(12)N-[7-{2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 184° to 188° C. (dec.).

I.R. (Nujol): 3400-3100, 1770, 1670, 1610, 1520 cm⁻¹

(13)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 145° to 150° C. (dec.).

I.R. (Nujol): 3350, 3220, 1775, 1670, 1620, 1525 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.22-2.15 (8H, m), 3.47-4.00 (4H, m), 4.10-4.57(4H, m), 4.57-4.90 (1H, m), 5.12 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and8 Hz), 8.10 (2H, broad s), 9.47 (1H, d, J=8 Hz)

(14)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[1-(2-hydroxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

I.R. (Nujol): 3350, 3250, 1775, 1675, 1620, 1525 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.90-2.47 (4H, m), 3.53-3.90 (4H, m), 4.13-4.53(4H, m), 5.10 (1H, d, J=5 Hz), 5.20-5.50 (1H, m), 5.63-6.23 (3H, m),8.12 (2H, broad s), 9.43 (1H, d, J=8 Hz)

(15)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1620, 1520 cm⁻¹

N.M.R. (DMSO-d₆, δ): 1.8-2.5 (4H, m), 3.67 (2H, broad s), 4.20 and 4.43(2H, ABq, J=15 Hz), 5.13 (1H, d, J=4 Hz), 5.3-5.5 (1H, m), 5.80 (1H, dd,J=4 and 8 Hz), 5.8-6.4 (2H, m), 8.13 (2H, s), 9.53 (1H, d, J=8 Hz)

EXAMPLE 60

To a solution ofN-[7-{2-t-butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer) (1.8 g) in formic acid (18 ml) was added conc. hydrochloricacid (0.5 ml) and the mixture was stirred for one hour at roomtemperature. The solvent was distilled off under reduced pressure andthe residue was pulverized with acetone, collected by filtration, washedwith acetone and diisopropyl ether to give a powder. The powder wasdissolved in water (5 ml) and subjected to column chromatography on anon ionic adsorption resin Diaion HP 20 (Trademark, prepared byMitsubishi Chemical Industries) (50 ml). After the column was washedwith water (500 ml), the elution was carried out with 40% aqueousmethanol. The eluates containing an object compound were collected,evaporated to remove methanol under reduced pressure and lyophilized togive white powder ofN-[7-{2-carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer) (800 mg), mp. 150° to 155° C. (dec.).

I.R. (Nujol): 3350, 3200, 1780, 1680, 1530 cm⁻¹

N.M.R. (D₂ O+NaHCO₃, δ): 3.27 and 3.63 (2H, ABq, J=18 Hz), 4.70 (2H, s),5.30 (1H, d, J=4 Hz), 5.40 and 5.60 (2H, ABq, J=14 Hz), 5.93 (1H, d, J=4Hz), 8.0-9.1 (5H, m)

EXAMPLE 61

The following compounds were obtained according to similar manners tothose of Examples 27, 47, 48 and 60.

(1)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

I.R. (Nujol): 3300, 3160, 1770, 1680, 1610, 1560, 1520 cm⁻¹

(2)N-[7-{2-(1-Carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

I.R. (Nujol): 3300, 3200, 1775, 1670, 1620, 1520 cm⁻¹

N.M.R. (D₂ O+NaHCO₃, δ): 1.50 (3H, d, J=7 Hz), 3.25 and 3.67 (2H, ABq,J=18 Hz), 4.40-4.90 (1H, m), 5.32 (1H, d, J=5 Hz), 5.42 and 5.60 (2H,ABq, J=15 Hz), 5.83-6.00 (1H, m), 7.9-9.1 (5H, m)

PREPARATION 40

The following compound was prepared according to a similar manner tothat of Preparation 17.2-Methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer), mp. 190°-193° C. (dec.).

IR (Nujol): 3380, 3280, 3180, 1750, 1710, 1610, 1510, 1260, 1230 cm⁻¹

NMR (DMSO-d₆, δ): 3.73 (3H, s), 4.87 (2H, s), 8.2 (2H, bs)

PREPARATION 41

To a suspension ofN-[7-(2-thienylacetamido)-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(27.0 g) and N,N-dimethylaniline (50.8 g) in methylene chloride (240 ml)was dropped trimethylsilyl chloride (26.0 g) under stirring and themixture was stirred for 1.5 hours at room temperature. To the resultingsolution was added phosphorous pentachloride (31.2 g) at -30° C. and themixture was stirred for one hour at -30° C. to -25° C. The mixture wasadded to a solution of n-butanol (120 g) in methylene chloride (240 ml)at -25° C. under stirring, and the stirring was continued for 1.5 hoursat room temperature. A resulting precipitate was collected byfiltration, washed with methylene chloride and dried on phosphorouspentoxide to giveN-[7-amino-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylatedihydrochloride (25.5 g), mp. 120° to 125° C. (dec.).

IR (Nujol): 1780, 1700, 1630 cm⁻¹

NMR (Dcl-D₂ O, δ): 3.60,3.83 (2H, ABq, J=18 Hz), 4.97 (2H, s), 5.33 (1H,d, J=5 Hz), 5.47 (1H, d, J=5 Hz), 5.60,5.93 (2H, ABq, J=14 Hz), 8.0-8.33(1H, m), 8.50-8.76 (1H, m), 8.83-9.16 (2H, m)

EXAMPLE 62 ##STR13##

To a cold solution of phosphorous pentachloride (1.46 g) in methylenechloride (30 ml) was added2-(1-methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (2.11 g) at -18° C. and the mixture was stirred for 30minutes at -14° to -11° C. To the reaction mixture was added dryn-hexane (90 ml) below -10° C. and the mixture was stirred for severalminutes and the solvent was removed by decantation. The residue wastriturated with n-hexane and collected by filtration to obtain a powderof the activated acid. On the other hand, a mixture ofN-[7-amino-3-cephem-3-ylmethyl]pyridinium-4-carboxylate dihydrochloride(2 g) and trimethylsilylacetamide (10 g) in methylene chloride wasstirred for 10 minutes at room temperature and cooled to -18° C. To thecold solution was added the powder obtained above and the mixture wasstirred for 30 minutes at - 13° to -10° C. and for 30 minutes at -5° to0° C. The reaction mixture was poured into an aqueous solution (100 ml)of sodium bicarbonate (3.6 g) and stirred for 15 minutes at roomtemperature and then adjusted to pH 1 with 6 N hydrochloric acid. Theaqueous layer was separated out, washed with ethyl acetate and subjectedto column chromatography on a non ionic adsorption resin, Diaion HP-20(100 ml). After the column was washed with water, 5% aqueous ethanol and10% aqueous ethanol successively, the elution was carried out with 20%aqueous ethanol. The eluates containing an object compound werecollected, evaporated to remove ethanol under reduced pressure andlyophilized to giveN-[7-{2-(1-methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer) (1.30 g), white powder, mp. 164° to 168° C. (dec.).

IR (Nujol): 3350-3150, 1770, 1720, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.15 (3H, t, J=7 Hz), 1.45 (6H, s), 3.03 and 3.55 (2H,ABq, J=18 Hz), 4.10 (2H, q, J=7 Hz), 5.11 (1H, d, J=5 Hz), 5.20 and 5.67(2H, ABq, J=13 Hz), 5.75 (1H, 2d, J=5 and 8 Hz), 8.20 (4H, m), 8.57 (1H,m), 9.47 (3H, m)

EXAMPLE 63

The following compounds were prepared according to the similar mannersto those of Examples 1 to 3, 5, 7 to 12, 32 to 34, 40, 57 and 62.

(1)7-[2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), powder, mp. 130° to 135° C. (dec.).

IR (Nujol): 3300, 1780, 1720, 1680, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.3-2.0 (8H, m), 2.15 (3H, s), 3.52 (2H, bs), 3.60(2H, s), 4.5-4.7 (1H, m), 4.77,5.00 (2H, ABq, J=14 Hz), 5.13 (1H, d, J=4Hz), 5.80 (1H, 2d, J=4 and 8 Hz), 8.10 (2H, s), 9.50 (1H, d, J=8 Hz)

(2)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1670, 1615, 1525 cm⁻¹

(3)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), white powder, mp. 160° to 165° C. (dec.).

IR (Nujol): 3260, 3170, 1770, 1655, 1610, 1520 cm⁻¹

(4)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-acetylpyridinium-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

IR (Nujol): 3270, 1770, 1700, 1670, 1610, 1520 cm⁻¹

(5)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-carboxymethylpyridinium-4-carboxylate(syn isomer), mp. 165° to 170° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1720, 1670, 1620, 1525 cm⁻¹

(6)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxyiminomethylpyridinium-4-carboxylate(syn isomer), mp. 140° to 145° C. (dec.).

IR (Nujol): 3280, 3160, 1770, 1680, 1630, 1610, 1520 cm⁻¹

(7)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-methyl-5'-(2-hydroxyethyl)thiazolium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

IR (Nujol): 3330, 1780, 1670, 1610, 1530 cm⁻¹

(8) Acetoxymethyl7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-2-methyl-3-cephem-4-carboxylate(syn isomer), mp. 183°-185° C. (dec.).

IR (Nujol): 3350, 3250, 1790, 1760, 1740, 1715, 1675, 1610, 1535 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (3H, d, J=7 Hz), 1.4-2.0 (8H, m), 2.08 (3H, s),3.6-4.1 (1H, m), 4.6-4.9 (1H, m), 5.17 (1H, d, J=5 Hz), 5.8-6.0 (3H, m),6.73 (1H, d, J=6 Hz), 8.16 (2H, s)

(9)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 135° to 140° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1775, 1735, 1710, 1675, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.93-2.47 (4H, m), 2.18 (3H, s), 3.55 (2H, bs), 3.65(2H, s), 4.80,5.07 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.23-5.53(1H, m), 5.70-6.23 (3H, m), 8.12 (2H, bs), 9.50 (1H, d, J=8 Hz)

(10)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxymethylpyridinium-4-carboxylate(synisomer), mp. 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1620, 1520 cm⁻¹

(11)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 143° to 148° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1610, 1520 cm⁻¹

(12)N-[7-{2-(2-Cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

IR (Nujol): 3300, 3200, 1775, 1660, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.5-2.0 (6H, m), 3.13,3.57 (2H, ABq, J=17 Hz), 4.6-4.7(1H, m), 5.07 (1H, d, J=4 Hz), 5.27,5.60 (2H, ABq, J=14 Hz), 5.80 (1H,2d, J=4 and 8 Hz), 5.77-6.0 (2H, m), 8.17 (2H, s), 8.0-8.4 (2H, m),8.43-8.80 (1H, m), 9.4-9.5 (2H, m), 9.55 (1H, d, J=8 Hz)

(13)7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 95° to 100° C. (dec.).

IR (Nujol): 3400, 3290, 3190, 1770, 1720, 1615, 1520 cm⁻¹

(14)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

(15)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm⁻¹

(16)N-[7-{2-Methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 165° to 170° C. (dec.).

IR (Nujol): 3300-3150,1760, 1670, 1620, 1520 cm⁻¹

NMR (D₂ O, δ): 3.17,3.70 (2H, ABq, J=18 Hz), 3.80 (3H, s), 4.93 (2H, s),5.30 (1H, d, J=5 Hz), 5.44,5.73 (2H, ABq, J=14 Hz), 5.93 (1H, d, J=5Hz), 8.10 (2H, m), 8.60 (1H, m), 8.98 (2H, m)

(17)N-[7-{2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1610 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.23 (3H, t, J=7 Hz), 3.11,3.67 (2H, ABq, J=18Hz), 4.23 (2H, q, J=7 Hz), 4.82 (4H, bs), 5.17 (1H, d, J=5 Hz),5.30,5.73 (2H, ABq, J=13 Hz), 5.83 (1H, d, J=5 Hz), 8.17 (1H, m), 8.60(1H, m), 9.23 (2H, m)

(18)7-[2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 105° to 110° C. (dec.).

IR (Nujol): 3350, 3250, 1780, 1720, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.43 (9H, s), 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H,s), 4.63 (2H, s), 4.82,5.05 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz),5.85 (1H, 2d, J=5 and 8 Hz), 8.15 (2H, bs), 9.53 (1H, d, J=8 Hz)

(19)N-[7-{2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

IR (Nujol): 3300, 1775, 1740, 1670, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.50 (9H, s), 3.23, 3.60 (2H, ABq, J=17 Hz),4.65 (2H, s), 4.80 (2H, s), 5.13 (1H, d, J=4 Hz), 5.37, 5.67 (2H, ABq,J=14 Hz), 5.80 (1H, d, J=4 Hz), 8.23 (2H, s), 8.0-8.27 (1H, m),8.43-8.67 (1H, m), 9.30-9.50 (2H, m)

(20)7-[2-(1-Carboxy)ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoxyacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), brownish powder, mp. 95° to 100° C. (dec.).

IR (Nujol): 3450, 3350, 3230, 1780, 1720, 1630, 1525 cm⁻¹

(21)7-[2-(1-t-Butoxycarbonyl)ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), brownish powder, mp. 110° to 115° C. (dec.).

IR (Nujol): 3400, 3300, 3200, 1780, 1720, 1620, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.40 (3H, d, J=7 Hz), 1.42 (9H, s), 2.17 (3H, s), 3.57(2H, bs), 3.63 (2H, s), 4.58-5.22 (3H, m), 5.17 (1H, d, J=5 Hz),5.73-5.97 (1H, m), 8.10 (2H, bs), 9.33-9.57 (1H, m)

(22)7-[2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

IR (Nujol): 3350, 3250, 1780, 1720, 1625, 1525 cm⁻¹

(23)N-[7-{2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), white powder, mp. 176° to 180° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm⁻¹

(24)N-[7-{2-(1-Methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1740, 1680 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.16 (3H, t, J=7 Hz), 1.48 (6H, s), 3.16,3.62(2H, ABq, J=18 Hz), 4.16 (2H, q, J=7 Hz), 4.80 (2H, s), 5.14 (1H, d, J=5Hz), 5.2-5.8 (2H, m), 5.80 (1H, d, J=5 Hz), 8.20 (1H, m), 8.56 (1H, m),9.32 (2H, m)

(25)7-[2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 140° to 145° C. (dec.).

IR (Nujol): 3350, 3250, 1785, 1720, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (6H, s), 1.50 (9H, s), 2.17 (3H, s), 3.57 (2H,bs), 3.63 (2H, s), 4.80,5.07 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=4 Hz),5.86 (1H, 2d, J=4 and 8 Hz), 8.13 (2H, s), 9.43 (1H, d, J=8 Hz)

(26)N-[7-{2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 176° to 180° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.40 (15H, bs), 3.08, 3.42 (2H, ABq, J=18 Hz),5.13 (1H, d, J=5 Hz), 5.40 (2H, m), 5.80 (1H, d, J=5 Hz), 8.17 (2H, m),8.65 (1H, m), 9.37 (2H, m)

EXAMPLE 64 ##STR14##

A mixture of 3-hydroxymethylpyridine (1.3 g) and potassium iodide (7.95g) in water (5.3 ml) was warmed to 60° C. under stirring and sodium7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]cephalosporanate(syn isomer) (5.32 g) was added thereto. The mixture was stirred for 5hours at 60° C. and diluted with a mixture of water (100 ml), ethylacetate (50 ml) and acetone (10 ml). The mixture was adjusted to pH 1with 6 N hydrochloric acid and the aqueous layer was separated out. Theaqueous solution was evaporated to remove acetone and ethyl acetate andsubjected to column chromatography on a non ionic adsorption resin,Diaion HP20 (160 ml). After the column was washed with water (500 ml),the elution was carried out with 40% aqueous methanol. The eluatescontaining a object compound were collected, evaporated to removemethanol under reduced pressure and lyophilized to giveN-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer) (1.2 g), white powder, mp. 160° to 165° C. (dec.).

IR (Nujol): 3260, 3170, 1770, 1655, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 3.17, 3.50 (2H, ABq, J=18 Hz),4.57-4.90 (3H, m), 5.08 (1H, d, J=5 Hz), 5.30, 5.65 (2H, ABq, J=14 Hz),5.70 (1H, 2d, J=5 and 8 Hz), 8.00-8.33 (3H, m), 8.33-8.67 (1H, m),9.17-9.43 (2H, m), 9.42 (1H, d, J=8 Hz)

EXAMPLE 65 ##STR15##

A mixture of7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) (2.8 g), sodium bicarbonate (420 mg), potassium iodide(28 g) and pyridine (590 mg) in water (28 ml) was stirred for one hourat 55° C. After cooling, ethyl acetate (20 ml), 1 N hydrochloric acid(5.5 ml) and acetone (10 ml) were added thereto under stirring. Theaqueous layer was separated out, washed with ethyl acetate andconcentrated to 30 ml under reduced pressure. An insoluble substance wasfiltered off and the filtrate was subjected to column chromatography ona non ionic adsorption resin, Diaion HP20 (100 ml). After the column waswashed with water (500 ml), the elution was carried out with 30% aqueousmethanol. The eluates containing a object compound were collected,evaporated to remove methanol under reduced pressure and lyophilized togive N-[7-{2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer)(620 mg), white powder, mp. 180° to 185° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1670, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.4-2.0 (8H, m), 3.17 3.53 (2H, ABq, J=18 Hz),4.60-4.83 (1H, m), 5.10 (1H, d, J=4 Hz), 5.30, 5.83 (2H, ABq, J=14 Hz),5.87 (1H, 2d, J=4 and 8 Hz), 8.17 (2H, s), 9.50 (1H, d, J=8 Hz), 8.0-9.7(5H, m)

EXAMPLE 66

The following compounds were prepared according to the similar mannersto those of Examples 14 to 17, 42, 64 and 65.

(1)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1670, 1615, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.20-2.00 (8H, m), 3.13, 3.50 (2H, ABq, J=18 Hz),4.57-4.98 (3H, m), 5.08 (1H, d, J=5 Hz) 5.25, 5.60 (2H, ABq, J=14 Hz),5.67 (1H, 2d, J=5 and 8 Hz), 8.05 (2H, d, J=6 Hz), 8.10 (2H, bs), 9.27(2H, d, J=6 Hz), 9.40 (1H, d, J=8 Hz)

(2)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-acetylpyridinium-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

IR (Nujol): 3270, 1770, 1700, 1670, 1610, 1520 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.33-2.00 (8H, m), 2.67 (3H, s), 3.07, 3.45 (2H,ABq, J=18 Hz), 4.50-4.77 (1H, m), 5.02 (1H, d, J=5 Hz), 5.25, 5.58 (2H,ABq, J=14 Hz), 5.63 (1H, d, J=5 Hz), 8.40 (2H, d, J=6 Hz), 9.52 (2H, d,J=6 Hz)

(3)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-carboxymethylpyridinium-4-carboxylate(syn isomer), mp. 165° to 170° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1720, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 1.30-2.00 (8H, m), 3.17, 3.52 (2H, ABq, J=18Hz), 3.93 (2H, s), 4.57-4.87 (1H, m), 5.07 (1H, d, J=5 Hz), 5.27, 5.63(2H, ABq, J=14 Hz), 5.70 (1H, d, J=5 Hz), 7.93-8.23 (1H, m), 8.37-8.63(1H, m), 9.10-9.37 (2H, m)

(4)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxyiminomethylpyridinium-4-carboxylate(syn isomer), mp. 140° to 145° C. (dec.).

IR (Nujol): 3280, 3160, 1770, 1680, 1630, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 3.23, 3.57 (2H, ABq, J=18 Hz),4.57-4.90 (1H, m), 5.12 (1H, d, J=5 Hz), 5.28, 5.65 (2H, ABq, J=14 Hz),5.73 (1H, 2d, J=5 and 8 Hz), 8.18 (2H, bs), 8.25 (2H, d, J=6 Hz), 8.42(1H, s), 9.35 (2H, d, J=6 Hz), 9.43 (1H, d, J=8 Hz)

(5)N-[7-{2-Cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-methyl-5'-(2-hydroxyethyl)thiazolium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

IR (Nujol): 3330, 1780, 1670, 1610, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.33-2.00 (8H, m), 2.57 (3H, s), 2.90-3.17 (2H, m),3.17-3.43 (2H, m), 3.57-3.80 (2H, m), 4.60-4.90 (1H, m), 5.07 (1H, d,J=5 Hz), 5.37 (2H, bs), 5.70 (1H, 2d, J=5 and 8 Hz), 8.17 (2H, bs), 9.43(1H, d, J=8 Hz), 10.23 (1H, s)

(6)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 140° to 145° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1620, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-2.5 (4H, m), 3.13, 3.50 (2H, ABq, J=18 Hz), 4.83(2H, s), 5.07 (1H, d, J=4 Hz), 5.20-5.40 (1H, m), 5.27, 5.67 (2H, ABq,J=14 Hz), 5.80 (1H, 2d, J=4 and 8 Hz), 5.87-6.20 (2H, m), 8.07 (2H, d,J=7 Hz), 8.17 (2H, s), 9.33 (2H, d, J=7 Hz), 9.47 (1H, d, J=8 Hz)

(7)N-[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 143° to 148° C. (dec.).

IR (Nujol): 3300, 3200, 1770, 1660, 1610, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 1.8-2.5 (4H, m), 3.13, 3.47 (2H, ABq, J=17 Hz), 4.73(2H, s), 5.35 (1H, d, J=4 Hz), 5.17-5.40 (1H, m), 5.40-6.20 (5H, m),8.13 (2H, s), 8.0-8.30 (1H, m), 8.37-8.60 (1H, m), 9.27-9.43 (2H, m),9.47 (1H, d, J=8 Hz)

(8)N-[7-{2-(2-Cyclohexen-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 150° to 155° C. (dec.).

IR (nujol): 3300, 3200, 1775, 1660, 1610, 1520 cm⁻¹

(9)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

(10)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm⁻¹

NMR (DMSO-d₆ -D₂ O, δ): 3.23, 3.55 (2H, ABq, J=18 Hz), 4.67 (2H, s),5.10 (1H, d, J=5 Hz), 5.35, 5.72 (2H, ABq, J=15 Hz), 5.80 (1H, d,J=5Hz), 8.43 (2H, d, J=6 Hz), 9.38 (2H, d, J=6 Hz)

(11)N-[7-{2-Methoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 165°-170° C. (dec.).

IR (Nujol): 3300-3150, 1760, 1670, 1620, 1520 cm⁻¹

(12)N-[7-{2-Ethoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1610 cm⁻¹

(13)N-[7-{2-t-Butoxycarbonylmethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 145° to 150° C. (dec.).

IR (Nujol): 3300, 1775, 1740, 1670, 1610, 1525 cm⁻¹

(14)N-[7-{2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), white powder, mp. 176° to 180° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm⁻¹

(15)N-[7-{2-(1-Methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), white powder, mp. 164° to 168° C. (dec.).

IR (Nujol): 3350-3150, 1700, 1720, 1670, 1620, 1520 cm⁻¹

(16)N-[7-{2-(1-Methyl-1-ethoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3400-3200, 1780, 1740, 1680 cm⁻¹

(17)N-[7-{2-(1-Methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]pyridinium-4-carboxylate(syn isomer), mp. 176° to 180° C. (dec.).

IR (Nujol): 3300, 3200, 1780, 1730, 1680, 1620, 1520 cm⁻¹

EXAMPLE 67 ##STR16##

To a cold mixture of trifluoroacetic acid (22 ml) and anisole (4.4 ml)was addedN-[7-{2-(1-methyl-1-t-butoxycarbonylethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-pyridinium-4-carboxylate(3.18 g) and the mixture was stirred for 40 minutes at room temperature.The mixture was evaporated to remove trifluoroacetic acid and theresidue was triturated with isopropyl ether to give a yellowish powder.The powder was dissolved in an aqueous sodium bicarbonate, adjusted topH 1 with 6 N hydrochloric acid and washed with ethyl acetate. Theaqueous solution was subjected to a column chromatography on a non ionicadsorption resin, Diaion HP-20 (140 ml). After the column was washedwith water, the elution was carried out with 5% and 10% aqueousisopropyl alcohol. The eluates containing an object compound werecollected, evaporated to remove isopropyl alcohol under reduced pressureand lyophilized to giveN-[7-{2-(1-methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-cephem-3-ylmethyl]pyridinium-4-carboxylate (syn isomer) (2.20 g), white powder,mp. 176° to 180° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.48 (6H, s), 3.10, 3.62 (2H, ABq, J=18 Hz),5.12 (1H, d, J=5 Hz), 5.45 (2H, m), 5.78 (1H, d, J=5 Hz), 8.13 (2H, m),8.58 (1H, m), 9.38 (2H, m)

EXAMPLE 68

The following compounds were prepared according to the similar mannersto those of Examples 27, 47, 48, 60 and 67.

(1)7-[2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 95° to 100° C. (dec.).

IR (Nujol): 3400, 3290, 3190, 1770, 1720, 1615, 1520 cm⁻¹

NMR (DMSO-d₆, δ): 2.17 (3H, s), 3.53 (2H, bs), 3.63 (2H, s), 4.67 (2H,s), 4.80, 5.07 (2H, ABq, J=13 Hz), 5.15 (1H, d, J=5 Hz), 5.87 (1H, 2d,J=5 and 8 Hz), 8.15 (2H, bs), 9.53 (1H, d, J=8 Hz)

(2)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-3'-hydroxymethylpyridinium-4-carboxylate(syn isomer), mp. 170° to 175° C. (dec.).

IR (Nujol): 3300, 1770, 1670, 1620, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.20, 3.50 (2H, ABq, J=18 Hz), 4.63 (2H, s),4.73 (2H, s), 5.07 (1H, d, J=4 Hz), 5.27, 5.60 (2H, ABq, J=14 Hz), 5.87(1H, d, J=4 Hz), 7.90-8.17 (1H, m), 8.37-8.60 (1H, m), 9.0-9.3 (2H, m)

(3)N-[7-{2-Carboxymethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-3-cephem-3-ylmethyl]-4'-carbamoylpyridinium-4-carboxylate(syn isomer), mp. 175° to 180° C. (dec.).

IR (Nujol): 3350, 3200, 1775, 1680, 1615, 1565, 1525 cm⁻¹

(4)7-[2-(1-Carboxy)ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), brownish powder, mp. 95° to 100° C. (dec.).

IR (Nujol): 3450, 3350, 3230, 1780, 1720, 1630, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.45 (3H, d, J=7 Hz), 2.20 (3H, s), 3.58 (2H, bs),3.67 (2H, s), 4.65-5.30 (3H, m), 5.22 (1H, d, J=5 Hz), 5.77-6.10 (1H,m), 8.23 (2H, bs), 9.40-9.68 (1H, m)

(5)7-[2-(1-Methyl-1-carboxyethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 180° to 185° C. (dec.).

IR (Nujol): 3350, 3250, 1780, 1720, 1625, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 1.47 (6H, s), 2.17 (3H, s), 3.55 (2H, bs), 3.62 (2H,s), 4.80, 5.03 (2H, ABq, J=14 Hz), 5.17 (1H, d, J=4 Hz), 5.87 (1H, 2d,J=4 and 8 Hz), 8.13 (2H, s), 9.47 (1H, d, J=8 Hz)

EXAMPLE 69

The following compounds were obtained according to similar manners tothose of Examples 1-3, 5, 7-12, 14-17, 32-34, 40, 42, 57, 62, 64 and 65.

(1)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3290, 3180, 1770, 1660, 1610, 1525 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.12, 3.50 (2H, ABq, J=18 Hz), 4.44-4.76 (2H,m), 5.10 (1H, d, J=5 Hz), 5.0-6.1 (6H, m), 8.0-8.4 (2H, m), 8.44-8.76(1H, m), 9.32-9.68 (2H, m)

(2)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 145° to 150° C. (dec.).

IR (Nujol): 3250, 2100, 1770, 1660, 1630, 1610, 1525 cm⁻¹

NMR (DMSO-d₆, δ): 3.10, 3.55 (2H, ABq, J=18 Hz), 3.47 (1H, t, J=2 Hz),4.73 (2H, d, J=2 Hz), 5.08 (1H, d, J=5 Hz), 5.25, 5.65 (2H, ABq, J=14Hz), 5.60-5.93 (1H, m), 8.0-8.4 (4H, m), 8.4-8.8 (1H, m), 9.3-9.7 (3H,m)

(3)7-[2-Hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 170° to 175° C. (dec.).

IR (Nujol): 3350, 3200, 1780, 1620, 1530, 1490 cm⁻¹

(4)7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 195° to 205° C. (dec.).

IR (Nujol): 3350-3150, 1770, 1670, 1620, 1520, 1150 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 2.17 (3H, s), 3.00, 3.62 (2H, ABq, J=18 Hz),5.10 (1H, d, J=5 Hz), 5.22 (2H, s), 5.73 (1H, d, J=5 Hz), 5.00-5.83 (2H,m), 8.13 (2H, m), 8.53 (1H, m), 9.33 (2H, m)

(5)7-[2-Trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 165° to 170° C. (dec.).

IR (Nujol): 3450, 1780, 1670, 1620, 1530, 1490 cm⁻¹

NMR (DMSO-d₆, δ): 3.18, 3.64 (2H, ABq, J=18 Hz), 5.18 (1H, d, J=5 Hz),5.34, 5.74 (2H, ABq, J=12 Hz), 5.92 (1H, dd, J=5 and 8 Hz), 7.28 (15H,s), 7.94-8.30 (4H, m), 8.42-8.66 (1H, m), 9.22-9.54 (2H, m), 9.78 (1H,d, J=8 Hz)

(6)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-)1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 150° to 155° C. (dec.).

IR (Nujol): 3300, 1780, 1675, 1630, 1530 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.23, 3.50 (2H, ABq, J=18 Hz), 4.63, 4.93 (2H,ABq, J=9 Hz), 5.17 (1H, d, J=5 Hz), 5.37, 5.73 (2H, ABq, J=14 Hz), 5.83(1H, d, J=5 Hz), 8.1-8.4 (2H, m), 8.5-8.8 (1H, m), 9.3-9.6 (2H, m)

(7)7-[2-(2-Oxotetrahydrofuran-3-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamio]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 140° to 145° C. (dec.).

IR (Nujol): 3350, 1780, 1670, 1620, 1530, 1490 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 2.43-2.83 (2H, m), 3.27, 3.63 (2H, ABq, J=18Hz), 4.23-4.67 (2H, m), 5.17-5.37 (1H, m), 5.20 (1H, d, J=5 Hz), 5.38,5.73 (2H, ABq, J=13 Hz), 5.87 (1H, d, J=5 Hz), 8.07-8.43 (2H, m),8.53-8.80 (1H, m), 9.23-9.50 (2H, m)

(8)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 161° to 165° C. (dec.).

IR (Nujol): 3400-3150, 1770, 1670, 1610, 1560, 1520 cm⁻¹

(9)7-[2-(2,2,2-Trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3300, 3150, 1780, 1680, 1610, 1580, 1520 cm⁻¹

(10)7-[2-Methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp 160° to 165° C. (dec.).

IR (Nujol): 3300, 3150, 1770, 1680, 1610, 1560, 1520 cm⁻¹

(11)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer), mp. 155° to 160° C. (dec.).

IR (Nujol): 3400, 3250, 3150, 2120, 1770, 1685, 1610, 1560, 1525 cm⁻¹

(12) Sodium7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer), mp 169° to 174° C. (dec.).

IR (Nujol): 3600-3100, 1760, 1690, 1665, 1640, 1610, 1520, 1005 cm⁻¹

(13)7-[2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 158° to 164° C. (dec.).

IR (Nujol): 3450-3150, 1770, 1680, 1630, 1510, 1260, 1180, 1100, 1030,1010 cm⁻¹

NMR (DMSO-d₆, δ): 2.0-2.6 (4H, m), 3.2-4.0 (2H, m), 3.62 (3H, s), 4.13,4.45 (2H, ABq, J=13 Hz), 5.13 (1H, d, J=5 Hz), 5.2-5.5 (1H, m), 5.7-6.0(2H, m), 6.0-6.2 (1H, m), 8.20 (2H, broad s), 9.50 (1H, d, J=8 Hz)

(14)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 161° to 166° C. (dec.).

IR (Nujol): 3260, 3180, 1770, 1670, 1620, 1520, 1335 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.48 (1H, s), 3.61 (3H, s), 3.3-3.9 (2H, m),4.10, 4.38 (2H, ABq, J=14 Hz), 4.77 (2H, s), 5.12 (1H, d, J=5 Hz), 5.78(1H, d, J=5 Hz)

(15)7-[2-Allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 169° to 173° C. (dec.).

IR (Nujol): 3360, 3210, 1775, 1670, 1625, 1560, 1520, 1250, 1175, 1100,1020 cm⁻¹

NMR (DMSO-d₆, δ): 3.3-4.0 (2H, m), 3.58 (3H, s), 4.0-4.6 (2H, m),4.5-4.8 (2H, m), 5.13 (1H, d, J=5 Hz), 5.0-5.6 (3H, m), 5.81 (1H, dd,J=5 and 9 Hz), 8.18 (2H, broad s), 9.53 (1H, d, J=9 Hz)

(16) Sodium7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer), mp 160° to 170° C. (dec.).

IR (Nujol): 3450, 3300, 3100, 1790, 1720, 1670, 1550 cm⁻¹

NMR (D₂ O, δ): 2.31 (3H, s), 3.33, 3.64 (2H, ABq, J=18 Hz), 4.6-5.1 (4H,m), 5.1-5.5 (2H, m), 5.20 (1H, d, J=5 Hz), 5.8-6.3 (1H, m), 5.84 (1H, d,J=5 Hz)

(17) Sodium7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer), mp 128° to 132° C. (dec.).

IR (Nujol): 3300, 1780, 1710, 1670, 1600, 1530 cm⁻¹

NMR (D₂ O, δ): 2.32 (3H, s), 3.50, 3.63 (2H, ABq, J=17 Hz), 4.60-5.07(4H, m), 5.23 (1H, d, J=4 Hz), 5.87 (1H, d, J=4 Hz)

(18) Sodium7-[2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylate(syn isomer), mp 180° to 190° C. (dec.).

IR (Nujol): 3500-3200, 1770, 1670, 1620, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 2.18 (3H, s), 2.20 (3H, s), 3.16, 3.48 (2H, ABq, J=18Hz), 3.58 (2H, s), 4.84, 5.08 (2H, ABq, J=12 Hz), 4.98 (1H, d, J=5 Hz),5.22 (2H, s), 5.62 (1H, dd, J=5 and 8 Hz), 8.14 (2H, broad s), 9.48 (1H,d, J=8 Hz)

(19)7-[2-(2-Propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer), mp 90° to 95° C. (dec.).

IR (Nujol): 3400, 3280, 3200, 2100, 1770, 1740, 1710, 1670, 1620 cm⁻¹

NMR (DMSO-d₆, δ): 2.18 (3H, s), 3.46 (1H, t, J=2 Hz), 3.46, 3.58 (2H,ABq, J=18 Hz), 3.62 (2H, s), 4.76 (2H, d, J=2 Hz), 4.78, 5.02 (2H, ABq,J=14 Hz), 5.12 (1H, d, J=5 Hz), 5.80 (1H, dd, J=5 and 8 Hz), 8.10 (2H,broad s), 9.60 (1H, d, J=8 Hz)

EXAMPLE 70

A mixture of7-[2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (5.55 g) and concentrated hydrochloric acid (2.3 ml) informic acid (60 ml) was stirred for two hours at ambient temperature.After an insoluble material was filtered off, the filtrate wasevaporated to dryness and the residue was pulverized with acetone andcollected by filtration. The powder was dissolved in water (13 ml) andsubjected to column chromatography on a non-ionic adsorption resinDiaion HP20 (Trademark, prepared by Mitsubishi Chemical Industries) (100ml), using water as an eluent. The eluates containing an object compoundwere collected and lyophilized to give yellowish white powder of7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer) (675 mg), mp 170° to 175° C. (dec.).

IR (Nujol): 3350, 3200, 1780, 1620, 1530, 1490 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 3.14, 3.54 (2H, ABq, J=18 Hz), 5.08 (1H, d, J=5Hz), 5.28, 5.62 (2H, ABq, J=12 Hz), 5.86 (1H, d, J=5 Hz), 7.96-8.24 (2H,m), 8.40-8.68 (1H, m), 9.16-9.42 (2H, m)

EXAMPLE 71 ##STR17##

To a cold solution of phosphorus pentachloride (20.8 g) in methylenechloride (375 ml) was added2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)aceticacid (syn isomer) (25.4 g) at -18° C. and the mixture was stirred for 40minutes at -12° to -10° C. To the reaction mixture was added diisopropylether (1.2 l) below -10° C. under stirring, which was continued untilthe mixture was warmed to ambient temperature. The resultingprecipitates were collected by filtration, washed with diisopropyl etherand then kept in a desiccator for several minutes. On the other hand, amixture of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridiniumchloride hydrochloride dihydrate (30.77 g) and trimethylsilylacetamide(154.5 g) in methylene chloride (800 ml) was warmed at 35° C. to make asolution, which was cooled to -18° C. To the cold solution were addedthe precipitates prepared above and the mixture was stirred for 30minutes at -12° to -10° C. A solution of sodium bicarbonate (26 g) inwater (400 ml) was added to the reaction mixture and the aqueous layerwas separated out, adjusted to pH 1.5 with 6 N hydrochloric acid, andwashed with ethyl acetate. The aqueous solution was adjusted to pH 4with an aqueous solution of sodium bicarbonate and passed through acolumn packed with acidic alumina (117 g). To the eluate (1.2 l) wereadded potassium thiocyanate (56.2 g) and sodium chloride (171.5 g) andthen the mixture was adjusted to pH 2.6 with 1 N hydrochloric acid undercooling in an ice-bath. After an insoluble material was filtered off,sodium chloride (171.5 g) was added to the filtrate and the solution wasadjusted to pH 1.6 with 1 N hydrochloric acid under stirring and coolingin an ice-bath. The resulting precipitates were filtered, washed withcold water (2×150 ml) and dried to give1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3-cephem-3-yl]methyl]pyridiniumthiocyanate (syn isomer) (28.1 g), mp 151° to 156° C. (dec.).

IR (Nujol): 2050, 1780, 1670, 1630, 1610, 1530 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.6-2.7 (4H, m), 3.33, 3.66 (2H, ABq, J=18 Hz),5.20 (1H, d, J=5 Hz), 4.9-6.3 (5H, m), 5.86 (1H, d, J=5 Hz), 8.2 (2H,m), 8.7 (1H, m), 9.15 (2H, m)

EXAMPLE 72

1-[[7-{2-(2-Cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3-cephem-3-yl]methyl]pyridiniumiodide (syn isomer) was obtained according to a similar manner to thatof Example 71 by using sodium iodide instead of potassium thiocyanate.

IR (Nujol): 3400-3100, 1775, 1670, 1620, 1520 cm⁻¹

NMR (DMSO-d₆ +D₂ O, δ): 1.6-2.8 (4H, m), 3.35, 3.80 (2H, ABq, J=19 Hz),5.31 (1H, d, J=5 Hz), 5.93 (1H, d, J=5 Hz), 5.0-6.4 (5H, m), 8.28 (2H,m), 8.74 (1H, m), 9.15 (2H, m)

EXAMPLE 73

To a solution of1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3-cephem-3-yl]methyl]pyridiniumthiocyanate (syn isomer) (11.7 g) in dimethylformamide (30 ml) was addeda solution of lithium chloride (1.7 g) in methanol (20 ml) understirring, which was continued for 10 minutes at ambient temperature. Aninsoluble material was filtered, washed with dimethylformamide (6 ml)and then the filtrate and the washings were combined. The combinedsolution was added to acetone (300 ml) under stirring, which wascontinued for five minutes at ambient temperature. The resultingprecipitates were filtered, washed with acetone (40 ml×3) and dried invacuo to give1-[[7-{2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido}-4-carboxy-3-cephem-3-yl]methyl]pyridiniumchloride (syn isomer) (11.0 g).

IR (Nujol): 3400-3100, 1780, 1660, 1630, 1530 cm⁻¹

NMR (DMSO-d₆, δ): 1.6-2.6 (4H, m), 3.39, 3.61 (2H, ABq, J=18 Hz), 5.19(1H, d, J=5 Hz), 4.9-5.6 (2H, m), 5.64 (1H, broad s), 5.81 (1H, dd, J=5and 8 Hz), 5.7-6.2 (2H, m), 8.20 (2H, m), 8.64 (1H, m), 9.22 (2H, m),9.48 (1H, d, J=8 Hz)

What we claim is:
 1. 7-substituted-3-cephem and cepham-4-carboxylic acidof the formula: ##STR18## where R¹ is amino or a protected amino;R² ishydrogen, lower alkylthio(lower)alkyl, halo(lower)alkyl, ar(lower)alkyl,lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, orO containing 5-membered heterocyclic group substituted with an oxogroup; R³ is hydrogen; R⁴ is pyridinium(lower)alkyl orpyridinium(lower)alkyl substituted with carbamoyl; and R⁵ is COO⁻ ; orR⁴ is lower alkanoyl(lower)alkanoyloxy(lower)alkyl or 2-loweralkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio(lower)alkyl; andR⁵ is carboxy or protected carboxy; and the heavy solid line meanssingle or double bond; and pharmaceutically acceptable salt thereof. 2.Syn-isomer of a compound of claim
 1. 3. A compound of claim 2, whereinthe heavy solid line is double bond.
 4. A compound of claim 3, whereinR¹is amino; R² is hydrogen, lower alkylthio(lower)alkyl, halo(lower)alkyl,ar(lower)alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl,cyclo(lower)alkenyl, or O containing 5-membered heterocyclic groupsubstituted with oxo group(s); R³ is hydrogen; R⁴ ispyridinium(lower)alkyl which may be substituted with carbamoyl; and R⁵is COO⁻ ; or R⁴ is lower alkanoyl(lower)alkanoyloxy(lower)alkyl or2-loweralkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio(lower)alkyl; andR⁵ is carboxy.
 5. A compound of claim 4, whereinR² is hydrogen, loweralkylthio(lower)alkyl, trihalo(lower)alkyl, triphenyl(lower)alkyl, loweralkenyl, lower alkynyl, or tetrahydrofuryl substituted with an oxogroup, R⁴ is pyridinium (lower)alkyl which may be substituted withcarbamoyl; and R⁵ is COO⁻ ; or R⁴ is loweralkanoyl(lower)alkanoyloxy(lower)alkyl; and R⁵ is carboxy.
 6. A compoundof claim 5, whereinR⁴ is pyridinium(lower)alkyl which may be substitutedwith carbamoyl and R⁵ is COO⁻.
 7. A compound of claim 6, wherein R² ishydrogen, methylthiomethyl, trifluoroethyl, trityl, allyl, 2-propynyl or2-oxotetrahydrofuryl and R⁴ is pyridiniummethyl which may be substitutedwith carbamoyl.
 8. A compound of claim 7, which is7-[2-hydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 9. A compound of claim 7, which is7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 10. A compound of claim 7, which is7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 11. A compound of claim 7, which is7-[2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 12. A compound of claim 7, which is7-[2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 13. A compound of claim 7, which is7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 14. A compound of claim 7, which is7-[2-(2-oxotetrahydrofuran-3-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 15. A compound of claim 7, which is7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 16. A compound of claim 7, which is7-[2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 17. A compound of claim 7, which is7-[2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(4-carbamoyl-1-pyridiniomethyl)-3-cephem-4-carboxylate(syn isomer).
 18. A compound of claim 5, whereinR² is loweralkylthio(lower)alkyl, trihalo(lower)alkyl, lower alkenyl or loweralkynyl, R⁴ is lower alkanoyl(lower)alkanoyloxy(lower)alkyl and R⁵ iscarboxy.
 19. A compound of claim 18, whereinR² is methylthiomethyl,trifluoroethyl, allyl or 2-propynyl and R⁴ is acetoacetoxymethyl.
 20. Acompound of claim 4, whereinR² is lower alkenyl, lower alkynyl,cyclo(lower)alkyl or cyclo(lower)alkenyl, R⁴ is 2-loweralkyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthio(lower)alkyl and R⁵is carboxy.
 21. A compound of claim 20, whereinR² is allyl, 2-propynyl,cyclopentyl, or 2-cyclopenten-1-yl and R⁴ is2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazinylthiomethyl.
 22. Acompound of claim 21, which is7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).
 23. A compound of claim 21, which is7-[2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).
 24. A compound of claim 21, which is sodium7-[2-cyclopentyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer).
 25. A compound of claim 21, which is7-[2-(2-cyclopenten-1-yloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-(2-methyl-5-oxo-6-hydroxy-2,5-dihydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).
 26. A compound of claim 19, which is7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamidol]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) and its sodium salt.
 27. A compound of claim 19, whichis7-[2-(2,2,2-trifluoroethoxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn-isomer) and its sodium salt.
 28. A compound of claim 19 whichis7-[2-methylthiomethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer) and its sodium salt.
 29. A compound of claim 19, whichis7-[2-(2-propynyloxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-acetoacetoxymethyl-3-cephem-4-carboxylicacid (syn isomer).
 30. An antibacterial composition comprising aneffective amount of a compound of claim 1 or pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptable,substantially non-toxic carrier or excipient.